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Cai Q, Jing C, Wang X, Xing X, Liu W. STEAP Proteins: Roles in disease biology and potential for therapeutic intervention. Int J Biol Macromol 2025; 309:142797. [PMID: 40185436 DOI: 10.1016/j.ijbiomac.2025.142797] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/25/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Iron and copper are essential metal ions, and maintaining their metabolic balance is critical for organismal health. The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) protein family, comprising STEAP1, STEAP2, STEAP3, and STEAP4, plays a vital role in cellular metal homeostasis. These proteins are located on the cell membrane and are characterized by six transmembrane domains. With the exception of STEAP1, the STEAP proteins function as metal oxidoreductases due to their F420H2:NADP+ oxidoreductase (FNO)-like domain. However, STEAP1 contributes to metal metabolism through its heme group and interaction with other STEAP proteins. Beyond metal metabolism, STEAP proteins are involved in critical cellular processes, including the regulation of the cell cycle, proliferation, differentiation, and apoptosis. Notably, STEAP proteins are recognized as potential biomarkers and therapeutic targets in human cancers, particularly prostate cancer. This review outlines the structural features and functional roles of STEAP proteins in various diseases, including cancers, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and benign prostatic hyperplasia, with a focus on their potential for therapeutic intervention.
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Affiliation(s)
- Qiaomei Cai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xiangling Xing
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China.
| | - Wancheng Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China.
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Tang L, Que H, Wei Y, Yang T, Tong A, Wei X. Replicon RNA vaccines: design, delivery, and immunogenicity in infectious diseases and cancer. J Hematol Oncol 2025; 18:43. [PMID: 40247301 PMCID: PMC12004886 DOI: 10.1186/s13045-025-01694-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/23/2025] [Indexed: 04/19/2025] Open
Abstract
Replicon RNA (RepRNA) represents a cutting-edge technology in the field of vaccinology, fundamentally transforming vaccine design and development. This innovative approach facilitates the induction of robust immune responses against a range of infectious diseases and cancers. RepRNA vaccines leverage the inherent capabilities of RNA-dependent RNA polymerase associated with self-replicating repRNA, allowing for extreme replication within host cells. This process enhances antigen production and subsequently stimulates adaptive immunity. Additionally, the generation of double-stranded RNA during RNA replication can activate innate immune responses. Numerous studies have demonstrated that repRNA vaccines elicit potent humoral and cellular immune responses that are broader and more durable than those generated by conventional mRNA vaccines. These significant immune responses have been shown to provide protection in various models for infectious diseases and cancers. This article will explore the design and delivery of RepRNA vaccines, the mechanisms of immune activation, preclinical studies addressing infectious diseases and tumors, and related clinical trials that focus on safety and immunogenicity.
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Affiliation(s)
- Lirui Tang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Haiying Que
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Ting Yang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, People's Republic of China.
| | - Aiping Tong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
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Zhang L, Ren X, An R, Song H, Tian Y, Wei X, Shi M, Wang Z. The Role of STEAP1 in Prostate Cancer: Implications for Diagnosis and Therapeutic Strategies. Biomedicines 2025; 13:794. [PMID: 40299363 PMCID: PMC12024770 DOI: 10.3390/biomedicines13040794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/21/2025] [Accepted: 03/23/2025] [Indexed: 04/30/2025] Open
Abstract
Prostate cancer (PCa) is one of the most common malignancies and the second leading cause of cancer-related death in men worldwide. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is exceptionally overexpressed in PCa, maintaining high expression even in the castration-resistant prostate cancer (CRPC) stage, making it a promising target for diagnosis and treatment. STEAP1-positive extracellular vesicles and STEAP1-PET imaging are optimistic approaches for the non-invasive detection of different stages of PCa. STEAP1-targeted therapy includes an antibody-drug conjugate (ADC), chimeric antigen receptor T cell (CAR-T), T-cell engager (TCE), and vaccines, which demonstrate valuable therapeutic prospects. This review presents the structure and pathophysiological function of STEAP1, synthesizes cutting-edge advances in STEAP1-targeted molecular imaging and clinical applications, and critically analyzes their translational potential to overcome the limitations of current PCa diagnosis and treatment.
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Affiliation(s)
- Lingling Zhang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
| | - Xinyi Ren
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
| | - Ran An
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
| | - Hongchen Song
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
| | - Yaqi Tian
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
| | - Xuan Wei
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
| | - Mingjun Shi
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
- Institute of Urology, Beijing Municipal Health Commission, Beijing 100054, China
| | - Zhenchang Wang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (L.Z.); (X.R.); (R.A.); (Y.T.); (X.W.)
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Delgado-Almenta V, Blaya-Cánovas JL, Calahorra J, López-Tejada A, Griñán-Lisón C, Granados-Principal S. Cancer Vaccines and Beyond: The Transformative Role of Nanotechnology in Immunotherapy. Pharmaceutics 2025; 17:216. [PMID: 40006583 PMCID: PMC11859086 DOI: 10.3390/pharmaceutics17020216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/20/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality globally, responsible for approximately 10 million deaths in 2022 and an estimated 21 million new cases in 2024. Traditional cancer treatments such as surgery, radiation therapy, and chemotherapy often present limitations in efficacy and side effects. However, immunotherapeutic vaccines have emerged as a promising approach, leveraging the body's immune system to target and eliminate cancer cells. This review examines the evolving landscape of cancer vaccines, differentiating between preventive and therapeutic strategies and highlighting the significance of tumor-specific antigens, including tumor-associated antigens (TAAs) and neoantigens. Recent advancements in vaccine technology, particularly through nanotechnology, have resulted in the development of nanovaccines, which enhance antigen stability, optimize delivery to immune cells, and promote robust immune responses. Notably, clinical data indicate that patients receiving immune checkpoint inhibitors can achieve overall survival rates of approximately 34.8 months compared to just 15.7 months for traditional therapies. Despite these advancements, challenges remain, such as the immunosuppressive tumor microenvironment and tumor heterogeneity. Emerging evidence suggests that combining nanovaccines with immunomodulators may enhance therapeutic efficacy by overcoming these obstacles. Continued research and interdisciplinary collaboration will be essential to fully exploit the promise of nanovaccines, ultimately leading to more effective and accessible treatments for cancer patients. The future of cancer immunotherapy appears increasingly hopeful as these innovative strategies pave the way for enhanced patient outcomes and an improved quality of life in oncology.
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Affiliation(s)
- Violeta Delgado-Almenta
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
| | - Jose L. Blaya-Cánovas
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Jesús Calahorra
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Araceli López-Tejada
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
| | - Carmen Griñán-Lisón
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), Centro de Investigación Biomédica (CIBM), University of Granada, 18016 Granada, Spain
| | - Sergio Granados-Principal
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
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Lundstrom K. Self-amplifying RNA virus vectors for drug delivery. Expert Opin Drug Deliv 2025; 22:181-195. [PMID: 39757959 DOI: 10.1080/17425247.2024.2445675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/09/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
INTRODUCTION Viral vectors have proven useful for delivering genetic information, such as drugs and vaccines, for therapeutic and prophylactic interventions. Self-amplifying RNA viruses possess the special feature of high-level RNA amplification in the host cell cytoplasm providing high antigen production against infectious pathogens and various types of cancers, and expression of anti-tumor genes, toxic genes, and immunostimulatory genes. AREAS COVERED Self-amplifying RNA viral vectors have been evaluated in animal models and clinical trials for immune responses and protection against challenges with pathogenic infectious agents and tumor cells. Likewise, immune responses, tumor regression, and tumor eradication have been monitored in preclinical and clinical settings. The literature search used in the review is based on PubMed and clinical trial/biotechnology company websites up until September 2024. EXPERT OPINION Self-amplifying RNA viruses have elicited strong immune responses and vaccine efficacy in animal models and humans leading to the approval of the vesicular stomatitis virus-based vaccine against Ebola virus disease in both the US and Europe. Moreover, therapeutic and prophylactic efficacy has been demonstrated in animal tumor models and cancer patients. Self-amplifying RNA viruses have also been evaluated in mouse models for neurological disorders.
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Fu D, Zhang X, Zhou Y, Hu S. A novel prognostic signature and therapy guidance for hepatocellular carcinoma based on STEAP family. BMC Med Genomics 2024; 17:16. [PMID: 38191397 PMCID: PMC10775544 DOI: 10.1186/s12920-023-01789-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/26/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND The six-transmembrane epithelial antigen of prostate (STEAP) family members are known to be involved in various tumor-related biological processes and showed its huge potential role in tumor immunotherapy. METHODS Biological differences were investigated through Gene set enrichment analysis (GSEA) and tumor microenvironment analysis by CIBERSORT. Tumor mutation burden (TMB), immunotherapy response and chemotherapeutic drugs sensitivity were estimated in R. RESULTS We established a prognostic signature with the formula: risk score = STEAP1 × 0.3994 + STEAP4 × (- 0.7596), which had a favorable concordance with the prediction. The high-risk group were enriched in cell cycle and RNA and protein synthesis related pathways, while the low-risk group were enriched in complement and metabolic related pathways. And the risk score was significantly correlated with immune cell infiltration. Most notably, the patients in the low-risk group were characterized with increased TMB and decreased tumor immune dysfunction and exclusion (TIDE) score, indicating that these patients showed better immune checkpoint blockade response. Meanwhile, we found the patients with high-risk were more sensitive to some drugs related to cell cycle and apoptosis. CONCLUSIONS The novel signature based on STEAPs may be effective indicators for predicting prognosis, and provides corresponding clinical treatment recommendations for HCC patients based on this classification.
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Affiliation(s)
- Dongxue Fu
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xian Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China
| | - Yi Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China
| | - Shanshan Hu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China.
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Hu C, Liu J, Cheng F, Bai Y, Mao Q, Xu M, Liang Z. Amplifying mRNA vaccines: potential versatile magicians for oncotherapy. Front Immunol 2023; 14:1261243. [PMID: 37936701 PMCID: PMC10626473 DOI: 10.3389/fimmu.2023.1261243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/10/2023] [Indexed: 11/09/2023] Open
Abstract
Cancer vaccines drive the activation and proliferation of tumor-reactive immune cells, thereby eliciting tumor-specific immunity that kills tumor cells. Accordingly, they possess immense potential in cancer treatment. However, such vaccines are also faced with challenges related to their design and considerable differences among individual tumors. The success of messenger RNA (mRNA) vaccines against coronavirus disease 2019 has prompted the application of mRNA vaccine technology platforms to the field of oncotherapy. These platforms include linear, circular, and amplifying mRNA vaccines. In particular, amplifying mRNA vaccines are characterized by high-level and prolonged antigen gene expression at low doses. They can also stimulate specific cellular immunity, making them highly promising in cancer vaccine research. In this review, we summarize the research progress in amplifying mRNA vaccines and provide an outlook of their prospects and future directions in oncotherapy.
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Affiliation(s)
- Chaoying Hu
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Jianyang Liu
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Feiran Cheng
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Yu Bai
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Qunying Mao
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Miao Xu
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Zhenglun Liang
- Division of Hepatitis and Enterovirus Vaccines, National Institutes for Food and Drug Control, Beijing, China
- National Health Commission (NHC), Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China
- National Medical Products Administration (NMPA), Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China
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Pampeno C, Hurtado A, Opp S, Meruelo D. Channeling the Natural Properties of Sindbis Alphavirus for Targeted Tumor Therapy. Int J Mol Sci 2023; 24:14948. [PMID: 37834397 PMCID: PMC10573789 DOI: 10.3390/ijms241914948] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/21/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies that support the targeted delivery of Sindbis vectors to tumor cells, highlighting their effectiveness in expressing tumor-associated antigens and immunomodulating proteins. Among the various alphavirus vectors developed for cancer therapy, Sindbis-vector-based imaging studies have been particularly extensive. Imaging modalities that enable the in vivo localization of Sindbis vectors within lymph nodes and tumors are discussed. The correlation between laminin receptor expression, tumorigenesis, and Sindbis virus infection is examined. Additionally, we present alternative entry receptors for Sindbis and related alphaviruses, such as Semliki Forest virus and Venezuelan equine encephalitis virus. The review also discusses cancer treatments that are based on the alphavirus vector expression of anti-tumor agents, including tumor-associated antigens, cytokines, checkpoint inhibitors, and costimulatory immune molecules.
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Affiliation(s)
| | | | | | - Daniel Meruelo
- Department of Pathology, NYU Grossman School of Medicine, New York University, New York, NY 10016, USA
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Lundstrom K. Alphaviruses in cancer immunotherapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 379:143-168. [PMID: 37541722 DOI: 10.1016/bs.ircmb.2023.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/06/2023]
Abstract
Alphaviruses have frequently been engineered for cancer therapy, cancer immunotherapy, and cancer vaccine development. As members of self-replicating RNA viruses, alphaviruses provide high levels of transgene expression through efficient self-amplifying of their RNA genome in host cells. Alphavirus vectors can be used as recombinant viral particles or oncolytic viruses. Alternatively, either naked or nanoparticle-encapsulated RNA and DNA replicons can be utilized. In the context of cancer prevention and treatment, antitumor, cytotoxic and suicide genes have been expressed from alphavirus vectors to provide tumor regression and tumor eradication. Moreover, immunostimulatory genes such as cytokines and chemokines have been used for cancer immunotherapy approaches. Expression of tumor antigens has been applied for cancer vaccine development. Alphavirus vectors has demonstrated tumor regression and even cure in various preclinical animal models. Immunization has elicited strong immune responses and showed protection against challenges with tumor cells in animal models. Several clinical trials have confirmed good safety and tolerability of alphaviruses in cancer patients although therapeutic efficacy will still require optimization.
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Dailey GP, Crosby EJ, Hartman ZC. Cancer vaccine strategies using self-replicating RNA viral platforms. Cancer Gene Ther 2023; 30:794-802. [PMID: 35821284 PMCID: PMC9275542 DOI: 10.1038/s41417-022-00499-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 05/21/2022] [Accepted: 06/23/2022] [Indexed: 11/09/2022]
Abstract
The development and success of RNA-based vaccines targeting SARS-CoV-2 has awakened new interest in utilizing RNA vaccines against cancer, particularly in the emerging use of self-replicating RNA (srRNA) viral vaccine platforms. These vaccines are based on different single-stranded RNA viruses, which encode RNA for target antigens in addition to replication genes that are capable of massively amplifying RNA messages after infection. The encoded replicase genes also stimulate innate immunity, making srRNA vectors ideal candidates for anti-tumor vaccination. In this review, we summarize different types of srRNA platforms that have emerged and review evidence for their efficacy in provoking anti-tumor immunity to different antigens. These srRNA platforms encompass the use of naked RNA, DNA-launched replicons, viral replicon particles (VRP), and most recently, synthetic srRNA replicon particles. Across these platforms, studies have demonstrated srRNA vaccine platforms to be potent inducers of anti-tumor immunity, which can be enhanced by homologous vaccine boosting and combining with chemotherapies, radiation, and immune checkpoint inhibition. As such, while this remains an active area of research, the past and present trajectory of srRNA vaccine development suggests immense potential for this platform in producing effective cancer vaccines.
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Affiliation(s)
| | | | - Zachary C Hartman
- Department of Surgery, Duke University, Durham, NC, USA.
- Department of Pathology, Duke University, Durham, NC, USA.
- Department of Immunology, Duke University, Durham, NC, USA.
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Loukinov D, Anderson AL, Mkrtichyan M, Ghochikyan A, Rivero-Hinojosa S, Tucker J, Lobanenkov V, Agadjanyan MG, Nelson EL. A Therapeutic Vaccine Targeting Rat BORIS (CTCFL) for the Treatment of Rat Breast Cancer Tumors. Int J Mol Sci 2023; 24:5976. [PMID: 36983050 PMCID: PMC10058450 DOI: 10.3390/ijms24065976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Cancer testis antigens are ideal for tumor immunotherapy due to their testis-restricted expression. We previously showed that an immunotherapeutic vaccine targeting the germ cell-specific transcription factor BORIS (CTCFL) was highly effective in treating aggressive breast cancer in the 4T1 mouse model. Here, we further tested the therapeutic efficacy of BORIS in a rat 13762 breast cancer model. We generated a recombinant VEE-VRP (Venezuelan Equine Encephalitis-derived replicon particle) vector-expressing modified rat BORIS lacking a DNA-binding domain (VRP-mBORIS). Rats were inoculated with the 13762 cells, immunized with VRP-mBORIS 48 h later, and then, subsequently, boosted at 10-day intervals. The Kaplan-Meier method was used for survival analysis. Cured rats were re-challenged with the same 13762 cells. We demonstrated that BORIS was expressed in a small population of the 13762 cells, called cancer stem cells. Treatment of rats with VRP-BORIS suppressed tumor growth leading to its complete disappearance in up to 50% of the rats and significantly improved their survival. This improvement was associated with the induction of BORIS-specific cellular immune responses measured by T-helper cell proliferation and INFγ secretion. The re-challenging of cured rats with the same 13762 cells indicated that the immune response prevented tumor growth. Thus, a therapeutic vaccine against rat BORIS showed high efficacy in treating the rat 13762 carcinoma. These data suggest that targeting BORIS can lead to the elimination of mammary tumors and cure animals even though BORIS expression is detected only in cancer stem cells.
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Affiliation(s)
- Dmitri Loukinov
- Molecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Amanda Laust Anderson
- Center for Immunology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92868, USA
| | | | | | | | - Jo Tucker
- Center for Immunology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92868, USA
| | - Victor Lobanenkov
- Molecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | | | - Edward L. Nelson
- Center for Immunology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92868, USA
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12
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Viral Vectors in Gene Therapy: Where Do We Stand in 2023? Viruses 2023; 15:v15030698. [PMID: 36992407 PMCID: PMC10059137 DOI: 10.3390/v15030698] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/23/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023] Open
Abstract
Viral vectors have been used for a broad spectrum of gene therapy for both acute and chronic diseases. In the context of cancer gene therapy, viral vectors expressing anti-tumor, toxic, suicide and immunostimulatory genes, such as cytokines and chemokines, have been applied. Oncolytic viruses, which specifically replicate in and kill tumor cells, have provided tumor eradication, and even cure of cancers in animal models. In a broader meaning, vaccine development against infectious diseases and various cancers has been considered as a type of gene therapy. Especially in the case of COVID-19 vaccines, adenovirus-based vaccines such as ChAdOx1 nCoV-19 and Ad26.COV2.S have demonstrated excellent safety and vaccine efficacy in clinical trials, leading to Emergency Use Authorization in many countries. Viral vectors have shown great promise in the treatment of chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, hemophilia, β-thalassemia, and sickle cell disease (SCD). Proof-of-concept has been established in preclinical studies in various animal models. Clinical gene therapy trials have confirmed good safety, tolerability, and therapeutic efficacy. Viral-based drugs have been approved for cancer, hematological, metabolic, neurological, and ophthalmological diseases as well as for vaccines. For example, the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, the oncolytic HSV T-VEC for melanoma, lentivirus-based treatment of ADA-SCID disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease have been approved for human use.
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13
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Alphaviruses in Immunotherapy and Anticancer Therapy. Biomedicines 2022; 10:biomedicines10092263. [PMID: 36140364 PMCID: PMC9496634 DOI: 10.3390/biomedicines10092263] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved.
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14
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STEAP1-4 (Six-Transmembrane Epithelial Antigen of the Prostate 1-4) and Their Clinical Implications for Prostate Cancer. Cancers (Basel) 2022; 14:cancers14164034. [PMID: 36011027 PMCID: PMC9406800 DOI: 10.3390/cancers14164034] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Despite recent therapeutic advances in the treatment of prostate cancer, metastatic castration-resistant prostate cancer continues to cause significant morbidity and mortality. New research into highly expressed proteins in metastatic castration-resistant prostate cancer shows that Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) are significant drivers of prostate cancer aggressiveness and metastasis. STEAP1, in particular, is highly expressed on the plasma membrane of prostate cancer cells and has received significant attention as a potential therapeutic target. This review highlights what is known about STEAP1–4 and identifies knowledge gaps that require further research. Abstract Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1–4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1–4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1–4 to provide context for past and current efforts to translate STEAP1–4 into the clinic.
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15
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Abstract
Self-replicating RNA viral vectors have been engineered for both prophylactic and therapeutic applications. Mainly the areas of infectious diseases and cancer have been targeted. Both positive and negative strand RNA viruses have been utilized including alphaviruses, flaviviruses, measles viruses and rhabdoviruses. The high-level of RNA amplification has provided efficient expression of viral surface proteins and tumor antigens. Immunization studies in animal models have elicit robust neutralizing antibody responses. In the context of infectious diseases, immunization with self-replicating RNA viral vectors has provided protection against challenges with lethal doses of pathogens in animal models. Similarly, immunization with vectors expressing tumor antigens has resulted in tumor regression and eradication and protection against tumor challenges in animal models. The transient nature and non-integration of viral RNA into the host genome are ideal features for vaccine development. Moreover, self-replicating RNA viral vectors show great flexibility as they can be applied as recombinant viral particles, RNA replicons or DNA replicon plasmids. Several clinical trials have been conducted especially in the area of cancer immunotherapy.
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16
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Su H, Imai K, Jia W, Li Z, DiCioccio RA, Serody JS, Poe JC, Chen BJ, Doan PL, Sarantopoulos S. Alphavirus Replicon Particle Vaccine Breaks B Cell Tolerance and Rapidly Induces IgG to Murine Hematolymphoid Tumor Associated Antigens. Front Immunol 2022; 13:865486. [PMID: 35686131 PMCID: PMC9171395 DOI: 10.3389/fimmu.2022.865486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
De novo immune responses to myeloid and other blood-borne tumors are notably limited and ineffective, making our ability to promote immune responses with vaccines a major challenge. While focus has been largely on cytotoxic cell-mediated tumor eradication, B-cells and the antibodies they produce also have roles in anti-tumor responses. Indeed, therapeutic antibody-mediated tumor cell killing is routinely employed in patients with hematolymphoid cancers, but whether endogenous antibody responses can be incited to blood-born tumors remains poorly studied. A major limitation of immunoglobulin therapies is that cell surface expression of tumor-associated antigen (TAA) targets is dynamic and varied, making promotion of polyclonal, endogenous B cell responses appealing. Since many TAAs are self-antigens, developing tumor vaccines that enable production of antibodies to non-polymorphic antigen targets remains a challenge. As B cell responses to RNA vaccines are known to occur, we employed the Viral Replicon Particles (VRP) which was constructed to encode mouse FLT3. The VRP-FLT3 vaccine provoked a rapid IgG B-cell response to this self-antigen in leukemia and lymphoma mouse models. In addition, IgGs to other TAAs were also produced. Our data suggest that vaccination with RNA viral particle vectors incites a loss of B-cell tolerance that enables production of anti-tumor antibodies. This proof of principle work provides impetus to employ such strategies that lead to a break in B-cell tolerance and enable production of broadly reactive anti-TAA antibodies as potential future therapeutic agents for patients with hematolymphoid cancers.
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Affiliation(s)
- Hsuan Su
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Kazuhiro Imai
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Wei Jia
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Zhiguo Li
- Biostatistics and Bioinformatics, Basic Science Department, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Rachel A DiCioccio
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Jonathan S Serody
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jonathan C Poe
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Benny J Chen
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Phuong L Doan
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Stefanie Sarantopoulos
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States.,Department of Immunology, School of Medicine, Duke University , Durham, NC, United States
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17
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Abstract
Alphaviruses have been engineered as expression vectors for different strategies of cancer therapy including immunotherapy and cancer vaccine development. Administration of recombinant virus particles, RNA replicons and plasmid DNA-based replicons provide great flexibility for alphavirus applications. Immunization and delivery studies have demonstrated therapeutic efficacy in the form of reduced tumor growth, tumor regression and eradication of established tumors in different animal models for cancers such as brain, breast, colon, cervical, lung, ovarian, pancreas, prostate cancers, and melanoma. Furthermore, vaccinated animals have showed protection against challenges with tumor cells. A limited number of clinical trials in the area of brain, breast, cervical, colon prostate cancers and melanoma vaccines has been conducted. Particularly, immunization of cervical cancer patients elicited immune responses and therapeutic activity in all patients included in a phase I clinical trial. Moreover, stable disease and partial responses were observed in breast cancer patients and prolonged survival was achieved in colon cancer patients.
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18
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Siddiqui A, Adnan A, Abbas M, Taseen S, Ochani S, Essar MY. Revival of the heterologous prime-boost technique in COVID-19: An outlook from the history of outbreaks. Health Sci Rep 2022; 5:e531. [PMID: 35229055 PMCID: PMC8866911 DOI: 10.1002/hsr2.531] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The heterologous prime-boost vaccination technique is not novel as it has a history of deployment in previous outbreaks. AIM Hence, this narrative review aims to provide critical insight for reviving the heterologous prime-boost immunization strategy for SARS-CoV-2 vaccination relative to a brief positive outlook on the mix-dose approach deployed in previous and existing outbreaks (ie, Ebola virus disease (EVD), malaria, tuberculosis, hepatitis B, HIV and influenza virus). METHODOLOGY AND MATERIALS A Boolean search was carried out to find the literature in MEDLINE-PubMed, Clinicaltrials, and Cochrane Central Register of Controlled Trials databases up till December 22, 2021, using the specific keywords that include "SARS-CoV2", "COVID-19", "Ebola," "Malaria," "Tuberculosis," "Human Immunodeficiency Virus," "Hepatitis B," "Influenza," "Mix and match," "Heterologous prime-boost," with interposition of "OR" and "AND." Full text of all the related articles in English language with supplementary appendix was retrieved. In addition, the full text of relevant cross-references was also retrieved. RESULTS Therefore, as generally evident by the primary outcomes, that is, safety, reactogenicity, and immunogenicity reported and updated by preclinical and clinical studies for addressing previous and existing outbreaks so far, including COVID-19, it is understood that heterologous prime-boost immunization has been proven successful for eliciting a more efficacious immune response as of yet in comparison to the traditional homologous prime-boost immunization regimen. DISCUSSION Accordingly, with increasing cases of COVID-19, many countries such as Germany, Pakistan, Canada, Thailand, and the United Kingdom have started administering the heterologous vaccination as the technique aids to rationalize the usage of the available vaccines to aid in the global race to vaccinate majority to curb the spread of COVID-19 efficiently. However, the article emphasizes the need for more large controlled trials considering demographic details of vaccine recipients, which would play an essential role in clearing the mistrust about safety concerns to pace up the acceptance of the technique across the globe. CONCLUSION Consequently, by combatting the back-to-back waves of COVID-19 and other challenging variants of concerns, including Omicron, the discussed approach can also help in addressing the expected evolution of priority outbreaks as coined by WHO, that is, "Disease X" in 2018 with competency, which according to WHO can turn into the "next pandemic" or the "next public health emergency," thus would eventually lead to eradicating the risk of "population crisis."
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Affiliation(s)
- Amna Siddiqui
- Department of MBBSKarachi Medical and Dental CollegeKarachi CityPakistan
| | - Alishba Adnan
- Department of MBBSKarachi Medical and Dental CollegeKarachi CityPakistan
| | - Munib Abbas
- Department of MBBSKarachi Medical and Dental CollegeKarachi CityPakistan
| | - Shafaq Taseen
- Department of MBBSKarachi Medical and Dental CollegeKarachi CityPakistan
| | - Sidhant Ochani
- Department of MBBSKhairpur Medical CollegeKhairpur Mir'sPakistan
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19
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Dorff TB, Narayan V, Forman SJ, Zang PD, Fraietta JA, June CH, Haas NB, Priceman SJ. Novel Redirected T-Cell Immunotherapies for Advanced Prostate Cancer. Clin Cancer Res 2022; 28:576-584. [PMID: 34675084 PMCID: PMC8866199 DOI: 10.1158/1078-0432.ccr-21-1483] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/21/2021] [Accepted: 09/13/2021] [Indexed: 01/07/2023]
Abstract
Immunotherapy has failed to achieve durable remissions in advanced prostate cancer patients. More potent T-cell-redirecting strategies may be needed to overcome the immunologically exclusive and suppressive tumor microenvironment. Clinical trials are underway, seeking to define the optimal target for T-cell redirection, such as PSMA, PSCA, or STEAP-1, as well as the optimal strategy, with CAR or bispecific antibodies. As results continue to emerge from these trials, understanding differential toxicity and efficacy of these therapies based on their targets and functional modifications will be key to advancing these promising therapies toward clinical practice. This review provides a unique depth and breadth of perspective regarding the diverse immunotherapy strategies currently under clinical investigation for men with advanced prostate cancer.
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Affiliation(s)
- Tanya B. Dorff
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Vivek Narayan
- Division of Hematology/Medical Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephen J. Forman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Peter D. Zang
- University of Southern California, Los Angeles, California
| | - Joseph A. Fraietta
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carl H. June
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Naomi B. Haas
- Division of Hematology/Medical Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Saul J. Priceman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California
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20
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Chen WJ, Wu HT, Li CL, Lin YK, Fang ZX, Lin WT, Liu J. Regulatory Roles of Six-Transmembrane Epithelial Antigen of the Prostate Family Members in the Occurrence and Development of Malignant Tumors. Front Cell Dev Biol 2021; 9:752426. [PMID: 34778263 PMCID: PMC8586211 DOI: 10.3389/fcell.2021.752426] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023] Open
Abstract
The human six-transmembrane epithelial antigen of the prostate (STEAP) proteins, which include STEAP1-4 and atypical STEAP1B, contain six transmembrane domains and are located in the cell membrane. STEAPs are considered archaeal metal oxidoreductases, based on their heme groups and F420H2:NADP+ oxidoreductase (FNO)-like structures, and play an important role in cell metal metabolism. Interestingly, STEAPs not only participate in biological processes, such as molecular transport, cell cycling, immune response, and intracellular and extracellular activities, but also are closely related to the occurrence and development of several diseases, especially malignant tumors. Up to now, the expression patterns of STEAPs have been found to be diverse in different types of tumors, with controversial participation in different aspects of malignancy, such as cell proliferation, migration, invasion, apoptosis, and therapeutic resistance. It is clinically important to explore the potential roles of STEAPs as new immunotherapeutic targets for the treatment of different malignant tumors. Therefore, this review focuses on the molecular mechanism and function of STEAPs in the occurrence and development of different cancers in order to understand the role of STEAPs in cancer and provide a new theoretical basis for the treatment of diverse cancers.
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Affiliation(s)
- Wen-Jia Chen
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Chun-Lan Li
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Yi-Ke Lin
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Ze-Xuan Fang
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Wen-Ting Lin
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Jing Liu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
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21
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Zhao Z, Wang Z, Song Z, Wu Y, Jin Q, Zhao Z. Predictive potential of STEAP family for survival, immune microenvironment and therapy response in glioma. Int Immunopharmacol 2021; 101:108183. [PMID: 34649092 DOI: 10.1016/j.intimp.2021.108183] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/08/2021] [Accepted: 09/19/2021] [Indexed: 10/20/2022]
Abstract
Glioma is the most commonly diagnosed primary tumor of central nervous system. Previous studies found that the six-transmembrane epithelial antigen of prostate (STEAP) family can regulate the biological behaviors of several cancers. However, the role of STEAP family in glioma remains unclear. Here, we systematically evaluated the relationship between STEAP family and prognosis of glioma patients in multiple cohorts. The analysis showed that dysregulation of STEAP family may affect cancer-immunity cycle, immune infiltration and phenotypes resulting in an immunosuppressive microenvironment in glioma. To accurately predict the prognosis of glioma patients, gene-based risk models were established based on the expression of STEAP1, 2 and 3. Multivariate and univariate Cox analyses demonstrated that the risk models could independently predict the prognosis of glioma. Finally, chemotherapy and immune therapy responses for high- and low-risk patients were predicted. In conclusion, this study systematically analyzed the role of STEAP family in glioma and established a model for predicting therapy response in patients with glioma.
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Affiliation(s)
- Zijun Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Zairan Wang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Zihan Song
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Yue Wu
- Department of Neurology, The Second Hospital of Hebei Medical University, Hebei, Shijiazhuang, China.
| | - Qianxu Jin
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Zongmao Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
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22
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Lundstrom K. Self-Replicating RNA Viruses for Vaccine Development against Infectious Diseases and Cancer. Vaccines (Basel) 2021; 9:1187. [PMID: 34696295 PMCID: PMC8541504 DOI: 10.3390/vaccines9101187] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/12/2021] [Accepted: 10/12/2021] [Indexed: 12/21/2022] Open
Abstract
Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered for recombinant protein expression and vaccine development. Due to the presence of RNA-dependent RNA polymerase activity, subgenomic RNA can replicate close to 106 copies per cell for translation in the cytoplasm providing extreme transgene expression levels, which is why they are named self-replicating RNA viruses. Expression of surface proteins of pathogens causing infectious disease and tumor antigens provide the basis for vaccine development against infectious diseases and cancer. Self-replicating RNA viral vectors can be administered as replicon RNA at significantly lower doses than conventional mRNA, recombinant particles, or DNA plasmids. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus, etc., showing robust immune response and protection in animal models. Recently, paramyxovirus and rhabdovirus vector-based SARS-CoV-2 vaccines as well as RNA vaccines based on self-amplifying alphaviruses have been evaluated in clinical settings. Vaccines against various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been developed. Clinical trials have shown good safety and target-specific immune responses. Ervebo, the VSV-based vaccine against Ebola virus disease has been approved for human use.
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23
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Fusion Protein Vaccine Based on Ag85B and STEAP1 Induces a Protective Immune Response against Prostate Cancer. Vaccines (Basel) 2021; 9:vaccines9070786. [PMID: 34358202 PMCID: PMC8310044 DOI: 10.3390/vaccines9070786] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 01/05/2023] Open
Abstract
(1) Background: There are currently limited treatments for castration-resistant prostate cancer. Immunotherapy involving Sipuleucel-T has increasingly drawn attention for prostate cancer management. BCG plays a vital role in treating bladder cancer, mainly by inducing immune activation, but is rarely used for prostate cancer. (2) Methods: The TCGA database, PCR, and Western blotting were used to analyze the expression of STEAP1 in mouse and human tissues. Then, we constructed a fusion protein vaccine with Mycobacterium tuberculosis Ag85B and three repeated octapeptide epitopes of a six-transmembrane epithelial antigen of the prostate 1 (STEAP1186-193), Ag85B-3×STEAP1186-193. The uptake of the fusion protein vaccine by DCs was evaluated by confocal microscopy, and DC markers were detected using flow cytometry after incubation with the fusion protein. The immune response against prostate cancer was evaluated by the LDH assay and xenografts in vitro and in vivo. Then, the tumor microenvironment was determined using IHC and ELISA. In addition, the epitope was mutated using CRISPR-Cas9 to illustrate that the fusion protein elicited immunization against STEAP1. (3) Results: The TCGA database analysis, PCR, and Western blotting showed that STEAP1 was highly expressed in human and murine prostate cancer. After the uptake of the purified fusion protein vaccine by DCs, CD11c, CD80, CD86, and MHC II were upregulated and triggered a cytotoxic T lymphocyte (CTL) response against TRAMP-C1 and RM1 cells in vitro. Furthermore, the fusion protein vaccine inhibited tumor growth and improved the tumor microenvironment in vivo, with more CD3+ cells and fewer FOXP3+ cells in the tumor. Serum IFN-γ and IL-2 were significantly higher than in the control group, while IL-4 expression was lower, indicating that the fusion protein vaccine activated Th1 immunity. The immune response against prostate cancer was greatly suppressed when the antigen targets were knocked out using CRISPR-Cas9. (4) Conclusion: In summary, our results provide the first evidence that a vaccine based on a fusion protein consisting of Ag85B and a prostate cancer octapeptide epitope with complete Freund’s adjuvant (CFA), triggers a robust immune response and inhibits tumor growth in murine prostate cancer.
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24
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Self-Replicating RNAs Drive Protective Anti-tumor T Cell Responses to Neoantigen Vaccine Targets in a Combinatorial Approach. Mol Ther 2020; 29:1186-1198. [PMID: 33278563 DOI: 10.1016/j.ymthe.2020.11.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/05/2020] [Accepted: 11/25/2020] [Indexed: 12/15/2022] Open
Abstract
Historically poor clinical results of tumor vaccines have been attributed to weakly immunogenic antigen targets, limited specificity, and vaccine platforms that fail to induce high-quality polyfunctional T cells, central to mediating cellular immunity. We show here that the combination of antigen selection, construct design, and a robust vaccine platform based on the Synthetically Modified Alpha Replicon RNA Technology (SMARRT), a self-replicating RNA, leads to control of tumor growth in mice. Therapeutic immunization with SMARRT replicon-based vaccines expressing tumor-specific neoantigens or tumor-associated antigen were able to generate polyfunctional CD4+ and CD8+ T cell responses in mice. Additionally, checkpoint inhibitors, or co-administration of cytokine also expressed from the SMARRT platform, synergized to enhance responses further. Lastly, SMARRT-based immunization of non-human primates was able to elicit high-quality T cell responses, demonstrating translatability and clinical feasibility of synthetic replicon technology for therapeutic oncology vaccines.
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Patra P, Bhattacharya M, Sharma AR, Ghosh P, Sharma G, Patra BC, Mallick B, Lee SS, Chakraborty C. Identification and Design of a Next-Generation Multi Epitopes Bases Peptide Vaccine Candidate Against Prostate Cancer: An In Silico Approach. Cell Biochem Biophys 2020; 78:495-509. [PMID: 32347457 DOI: 10.1007/s12013-020-00912-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/07/2020] [Indexed: 12/28/2022]
Abstract
Prostate cancer (PCa) is the second most diagnosed cancer in men and ranked fifth in overall cancer diagnosis. During the past decades, it has arisen as a significant life-threatening disease in men at an older age. At the early onset of illness when it is in localized form, radiation and surgical treatments are applied against this disease. In case of adverse situations androgen deprivation therapy, chemotherapy, hormonal therapy, etc. are widely used as a therapeutic element. However, studies found the occurrences of several side effects after applying these therapies. In current work, several immunoinformatic techniques were applied to formulate a multi-epitopic vaccine from the overexpressed antigenic proteins of PCa. A total of 13 epitopes were identified from the five prostatic antigenic proteins (PSA, PSMA, PSCA, STEAP, and PAP), after validation with several in silico tools. These epitopes were fused to form a vaccine element by (GGGGS)3 peptide linker. Afterward, 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) was used as an adjuvant to initiate and induce STING-mediated cytotoxic cascade. In addition, molecular docking was performed between the vaccine element and HLA class I antigen with the low ACE value of -251 kcal/mol which showed a significant binding. Molecular simulation using normal mode analysis (NMA) illustrated the docking complex as a stable one. Therefore, this observation strongly indicated that our multi epitopes bases peptide vaccine molecule will be an effective candidate for the treatment of the PCa.
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Affiliation(s)
- Prasanta Patra
- Department of Zoology, Vidyasagar University, Midnapore, West Bengal, 721102, India
| | - Manojit Bhattacharya
- Department of Zoology, Vidyasagar University, Midnapore, West Bengal, 721102, India
- Institute for Skeletal Aging & Orthopedic Surgery, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 24252, Republic of Korea
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 24252, Republic of Korea
| | - Pratik Ghosh
- Department of Zoology, Vidyasagar University, Midnapore, West Bengal, 721102, India
| | - Garima Sharma
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Bidhan Chandra Patra
- Department of Zoology, Vidyasagar University, Midnapore, West Bengal, 721102, India
| | - Bidyut Mallick
- Departments of Applied Science, Galgotias College of Engineering and Technology, Greater Noida, India
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 24252, Republic of Korea.
| | - Chiranjib Chakraborty
- Institute for Skeletal Aging & Orthopedic Surgery, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 24252, Republic of Korea.
- Adamas University, North, 24 Parganas, Kolkata, West Bengal, 700126, India.
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Lundstrom K. Application of Viral Vectors for Vaccine Development with a Special Emphasis on COVID-19. Viruses 2020; 12:E1324. [PMID: 33218001 PMCID: PMC7698750 DOI: 10.3390/v12111324] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/12/2022] Open
Abstract
Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens. Immunization studies in preclinical animal models have evaluated the elicited humoral and cellular responses and the possible protection against challenges with lethal doses of infectious pathogens or tumor cells. Several vaccine candidates for both infectious diseases and various cancers have been subjected to a number of clinical trials. Human immunization trials have confirmed safe application of viral vectors, generation of neutralizing antibodies and protection against challenges with lethal doses. A special emphasis is placed on COVID-19 vaccines based on viral vectors. Likewise, the flexibility and advantages of applying viral particles, RNA replicons and DNA replicon vectors of self-replicating RNA viruses for vaccine development are presented.
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Lundstrom K. Self-Amplifying RNA Viruses as RNA Vaccines. Int J Mol Sci 2020; 21:ijms21145130. [PMID: 32698494 PMCID: PMC7404065 DOI: 10.3390/ijms21145130] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 01/04/2023] Open
Abstract
Single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases.
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DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen. Acta Biomater 2019; 96:480-490. [PMID: 31299353 DOI: 10.1016/j.actbio.2019.07.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 06/17/2019] [Accepted: 07/03/2019] [Indexed: 11/23/2022]
Abstract
Castrate resistant prostate cancer (CRPC) remains a major challenge for healthcare professionals. Immunotherapeutic approaches, including DNA vaccination, hold the potential to harness the host's own immune system to mount a cell-mediated, anti-tumour response, capable of clearing disseminated tumour deposits. These anti-cancer vaccines represent a promising strategy for patients with advanced disease, however, to date DNA vaccines have demonstrated limited efficacy in clinical trials, owing to the lack of a suitable DNA delivery system. This study was designed to evaluate the efficacy of a two-tier delivery system incorporating cationic RALA/pDNA nanoparticles (NPs) into a dissolvable microneedle (MN) patch for the purposes of DNA vaccination against prostate cancer. Application of NP-loaded MN patches successfully resulted in endogenous production of the encoded Prostate Stem Cell Antigen (PSCA). Furthermore, immunisation with RALA/pPSCA loaded MNs elicited a tumour-specific immune response against TRAMP-C1 tumours ex vivo. Finally, vaccination with RALA/pPSCA loaded MNs demonstrated anti-tumour activity in both prophylactic and therapeutic prostate cancer models in vivo. This is further evidence that this two-tier MN delivery system is a robust platform for prostate cancer DNA vaccination. STATEMENT OF SIGNIFICANCE: This research describes the development and utilisation of our unique microneedle (MN) DNA delivery system, which enables penetration through the stratum corneum and deposition of the DNA within the highly immunogenic skin layers via a dissolvable MN matrix, and facilitates cellular uptake via complexation of pDNA cargo into nanoparticles (NPs) with the RALA delivery peptide. We report for the first time on using the NP-MN platform to immunise mice with encoded Prostate Stem Cell Antigen (mPSCA) for prostate cancer DNA vaccination. Application of the NP-MN system resulted in local mPSCA expression in vivo. Furthermore, immunisation with the NP-MN system induced a tumour-specific cellular immune response, and inhibited the growth of TRAMP-C1 prostate tumours in both prophylactic and therapeutic challenge models in vivo.
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Chen X, Wang R, Chen A, Wang Y, Wang Y, Zhou J, Cao R. Inhibition of mouse RM-1 prostate cancer and B16F10 melanoma by the fusion protein of HSP65 & STEAP1 186-193. Biomed Pharmacother 2019; 111:1124-1131. [PMID: 30841425 DOI: 10.1016/j.biopha.2019.01.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/20/2018] [Accepted: 01/05/2019] [Indexed: 01/28/2023] Open
Abstract
The research of tumor vaccine plays a crucial role in tumor immunotherapy. This study has constructed and prepared a fusion protein vaccine of heat shock protein 65 (HSP65) and the octapeptide epitope 186-193 of the six transmembrane epithelial antigen of the prostate 1 (STEAP1 186-193), and investigated the inhibitory effect of the fusion protein on mouse RM-1 prostate cancer and B16F10 melanoma xenografts. The fusion protein His-HSP65-STEAP1 186-193 (HHST1), His-HSP65-2×STEAP1 186-193 (HHST2) and His-HSP65-6×STEAP1 186-193 (HHST6) were obtained by setting different copy number of STEAP1 186-193 and adding His purification tag before HSP65. Firstly the inhibitory effect of fusion protein on mouse RM-1 prostate cancer xenografts has been studied, which could be the basis of the study the inhibitory effect of the best fusion protein on mouse B16F10 melanoma xenografts. All studies compared with the fusion protein His-HSP65 (HHSP65), the fusion proteins HHST1, HHST2 and HHST6 all could significantly inhibit the growth of mouse RM-1 prostate cancer xenografts. In addition, the fusion protein HHST2 was proved to be the best compared with the fusion proteins HHST1 and HHST6 (P<0.05). Apart from this, compared with the fusion protein HHSP65, the fusion protein HHST2 also significantly inhibited the growth of mouse beared B16F10 melanoma. The results above indicate that HSP65 and STEAP1 186-193 can significantly inhibit the growth of mouse RM-1 prostate cancer and B16F10 melanoma xenografts, and the appropriate increase of copy number can effectively improve that the fusion protein has an excellent anti-tumor ability.
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Affiliation(s)
- Xuan Chen
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Rui Wang
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Anji Chen
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Yongmei Wang
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Yiqin Wang
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Jialei Zhou
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China
| | - Rongyue Cao
- Microgene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, No. 24, Tongjia Alley, Central Road, Nanjing, 210009, China.
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Lundstrom K. Self-Replicating RNA Viruses for RNA Therapeutics. Molecules 2018; 23:molecules23123310. [PMID: 30551668 PMCID: PMC6321401 DOI: 10.3390/molecules23123310] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/10/2018] [Accepted: 12/11/2018] [Indexed: 12/23/2022] Open
Abstract
Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.
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Xie J, Yang Y, Sun J, Jiao Z, Zhang H, Chen J. STEAP1 Inhibits Breast Cancer Metastasis and Is Associated With Epithelial-Mesenchymal Transition Procession. Clin Breast Cancer 2018; 19:e195-e207. [PMID: 30253922 DOI: 10.1016/j.clbc.2018.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/24/2018] [Accepted: 08/24/2018] [Indexed: 12/22/2022]
Abstract
PURPOSE Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is a cell surface antigen overexpressed in multiple cancers and is associated with malignancy and disease prognosis. The aims of this study were to evaluate STEAP1 expression in breast cancer and to determine the mechanisms involved. METHODS STEAP1 expression was compared in normal breast tissue (n = 40), benign fibroadenoma (n = 52), and primary breast cancer (n = 211) using immunohistochemistry. Quantitative real-time polymerase chain reaction, Western blot analysis, and immunocytochemistry were used to evaluate STEAP1 expression in 3 breast cancer cell lines and in a normal mammary epithelial cell line. STEAP1 expression and its prognostic value in breast cancer were verified using the Oncomine and Kaplan-Meier Plotter databases. Transfection of cells to up-regulate or knock down STEAP1 expression was used to determine the effect of STEAP1 on cell invasion and proliferation, and to evaluate its relationship to epithelial-mesenchymal transition (EMT) progression. RESULTS STEAP1 expression was lower in breast cancers cells, and low expression was associated with a malignant phenotype and poor prognosis. Analysis of public databases supported our conclusions. Knockdown of STEAP1 expression enhanced cellular invasion and migration abilities, increased expression of EMT-related genes MMP2, MMP9, MMP13, VIM, and CDH2, and decreased CDH1 expression. Enhanced STEAP1 expression significantly inhibited cellular invasion and migration abilities, decreased expression of the EMT-related genes, and increased CDH1 expression. Up-regulation or knockdown of STEAP1 had little effect on cellular proliferation. CONCLUSION STEAP1 was down-regulated in breast cancer, inhibited metastasis of breast cancer, and hampered the levels of EMT markers, which thus implicated STEAP1 in the suppression of EMT.
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Affiliation(s)
- Jie Xie
- Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan, China
| | - Yan Yang
- Health Examination Center, Qilu Hospital, Shandong University, Jinan, China
| | - Jiali Sun
- Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan, China
| | - Zhi Jiao
- Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan, China
| | - Haozheng Zhang
- Research Institute of Pediatrics, Qilu Children's Hospital of Shandong University, Shandong University, Jinan, China
| | - Jie Chen
- Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan, China.
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Atherton MJ, Stephenson KB, Tzelepis F, Bakhshinyan D, Nikota JK, Son HH, Jirovec A, Lefebvre C, Dvorkin-Gheva A, Ashkar AA, Wan Y, Stojdl DF, Belanger EC, Breau RH, Bell JC, Saad F, Singh SK, Diallo JS, Lichty BD. Transforming the prostatic tumor microenvironment with oncolytic virotherapy. Oncoimmunology 2018; 7:e1445459. [PMID: 29900060 PMCID: PMC5993491 DOI: 10.1080/2162402x.2018.1445459] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.
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Affiliation(s)
- Matthew J. Atherton
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | | | - Fanny Tzelepis
- Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada
| | - David Bakhshinyan
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada
- Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Canada
| | | | - Hwan Hee Son
- Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada
| | - Anna Jirovec
- Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada
| | - Charles Lefebvre
- Stojdl Lab, CHEO Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Anna Dvorkin-Gheva
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Ali A. Ashkar
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Yonghong Wan
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - David F. Stojdl
- Turnstone Biologics, Ottawa, Canada
- Stojdl Lab, CHEO Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Eric C. Belanger
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada
| | | | - John C. Bell
- Turnstone Biologics, Ottawa, Canada
- Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada
| | - Fred Saad
- Department of Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Canada
| | - Sheila K. Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada
- Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Canada
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada
| | - Jean-Simone Diallo
- Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada
| | - Brian D. Lichty
- McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
- Turnstone Biologics, Ottawa, Canada
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Gomes IM, Rocha SM, Gaspar C, Alvelos MI, Santos CR, Socorro S, Maia CJ. Knockdown of STEAP1 inhibits cell growth and induces apoptosis in LNCaP prostate cancer cells counteracting the effect of androgens. Med Oncol 2018; 35:40. [PMID: 29464393 DOI: 10.1007/s12032-018-1100-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 02/15/2018] [Indexed: 12/26/2022]
Abstract
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is overexpressed in numerous types of tumors, especially in prostate cancer. STEAP1 is located in the plasma membrane of epithelial cells and may play an important role in inter- and intracellular communication. Several studies suggest STEAP1 as a potential biomarker and an immunotherapeutic target for prostate cancer. However, the role of STEAP1 in cell proliferation and apoptosis remains unclear. Therefore, the role of STEAP1 in prostate cancer cells proliferation and apoptosis was determined by inducing STEAP1 gene knockdown in LNCaP cells. In addition, the effect of DHT on the proliferation of LNCaP cells knocked down for STEAP1 gene was evaluated. Our results demonstrated that silencing the STEAP1 gene reduces LNCaP cell viability and proliferation, while inducing apoptosis. In addition, we showed that the cellular and molecular effects of STEAP1 gene knockdown may be independent of DHT treatment, and blocking STEAP1 may reveal to be an appropriate strategy to activate apoptosis in cancer cells, as well as to prevent the proliferative and anti-apoptotic effects of DHT in prostate cancer.
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Affiliation(s)
- Inês Margarida Gomes
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
| | - Sandra Moreira Rocha
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
| | - Carlos Gaspar
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
| | - Maria Inês Alvelos
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070, Brussels, Belgium
| | - Cecília Reis Santos
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
| | - Cláudio Jorge Maia
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal.
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Pollack SM. The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients. Expert Rev Vaccines 2018; 17:107-114. [PMID: 29280411 PMCID: PMC6521962 DOI: 10.1080/14760584.2018.1419068] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Synovial Sarcoma (SS) and Myxoid Round Cell Liposarcoma (MRCL) are devastating sarcoma subtypes with few treatment options and poor outcomes in the advanced setting. However, both these diseases may be ideal for novel immunotherapies targeting the cancer-testis antigen, NY-ESO-1. AREAS COVERED In this review, we discuss the novel NY-ESO-1 targeted vaccine regimen, CMB305. This regimen uses a unique integration-deficient, dendritic-cell targeting lentiviral vector from the ZVex® platform, LV305, in order to prime NY-ESO-1 specific T cells. LV305 has single agent activity, and, in one case, caused a durable partial response in a refractory SS patient. CMB305 also includes a boost from a NY-ESO-1 protein vaccine given along with a potent toll-like-4 receptor agonist, glycopyranosyl lipid A. CMB305 induces NY-ESO-1 specific T cell responses in both SS and MRC patients and these patients had excellent overall survival (OS) outcomes in the initial phase I study. EXPERT COMMENTARY CMB305 is a therapeutic vaccine regimen targeting NY-ESO-1 based on the lentiviral vaccine vector, LV305. Phase I studies have proven this vaccine is active immunologically. Data suggesting this vaccine may improve OS for SS and MRCL patients is exciting but early, and on-going work is testing the impact of CMB305 on patient outcomes.
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Affiliation(s)
- Seth M Pollack
- a Clinical Research Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA
- b Department of Medicine , University of Washington , Seattle , WA , USA
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García-Hernández MDLL, Uribe-Uribe NO, Espinosa-González R, Kast WM, Khader SA, Rangel-Moreno J. A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression. Front Immunol 2017; 8:563. [PMID: 28567040 PMCID: PMC5434117 DOI: 10.3389/fimmu.2017.00563] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 04/27/2017] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Multiple solid cancers contain tertiary lymphoid organs (TLO). However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function. METHODS We used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer) or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17), tumor-infiltrating immune cells (mature DC-LAMP+ dendritic cells, CD3+ T cells, CD3+Foxp3+ regulatory T cells (Treg), T bet+ Th1 cells, granzyme B+ cytotoxic cells), and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV), stromal cells), which promote prostate tumor growth or are critical components of tumor-associated TLO. RESULTS Generally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet+ T cells and CD8 T cells were abundant in tumor-associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2). Finally, consistent with tumor regression, prostate stem cell antigen was considerably reduced in TLO and tumor areas from evanescent carcinoma patients. CONCLUSION Collectively, our results suggest that COX2 and Treg are attractive therapeutic targets that can be harnessed to enhance TLO-driven tumor immunity against prostate cancer. Specially, the presence of HEV and lymphatics indicate that TLO can be used as a platform for delivery of cell-based and/or COX2 blocking therapies to improve control of tumor growth in prostate cancer.
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Affiliation(s)
| | - Norma Ofelia Uribe-Uribe
- Department of Anatomy and Anatomical Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Ricardo Espinosa-González
- Department of Anatomy and Anatomical Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - W. Martin Kast
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Shabaana A. Khader
- Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO, USA
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Replicon RNA Viral Vectors as Vaccines. Vaccines (Basel) 2016; 4:vaccines4040039. [PMID: 27827980 PMCID: PMC5192359 DOI: 10.3390/vaccines4040039] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/14/2016] [Accepted: 10/28/2016] [Indexed: 12/22/2022] Open
Abstract
Single-stranded RNA viruses of both positive and negative polarity have been used as vectors for vaccine development. In this context, alphaviruses, flaviviruses, measles virus and rhabdoviruses have been engineered for expression of surface protein genes and antigens. Administration of replicon RNA vectors has resulted in strong immune responses and generation of neutralizing antibodies in various animal models. Immunization of mice, chicken, pigs and primates with virus-like particles, naked RNA or layered DNA/RNA plasmids has provided protection against challenges with lethal doses of infectious agents and administered tumor cells. Both prophylactic and therapeutic efficacy has been achieved in cancer immunotherapy. Moreover, recombinant particles and replicon RNAs have been encapsulated by liposomes to improve delivery and targeting. Replicon RNA vectors have also been subjected to clinical trials. Overall, immunization with self-replicating RNA viruses provides high transient expression levels of antigens resulting in generation of neutralizing antibody responses and protection against lethal challenges under safe conditions.
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Abstract
RNA viruses are characterized by their efficient capacity to replicate at high levels in mammalian cells leading to high expression of foreign genes and making them attractive candidates for vectors engineered for vaccine development and gene therapy. Particularly, alphaviruses, flaviviruses, rhabdoviruses and measles viruses have been applied for immunization against infectious agents and tumors. Application of replicon RNA, DNA/RNA-layered vectors and replication-deficient viral particles have provided strong immune responses and protection against challenges with lethal doses of viral pathogens or tumor cells. Moreover, tumor regression has been obtained when RNA replicons have been administered in the form of RNA, DNA and viral particles, including replication-proficient oncolytic particles.
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38
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Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination with PD-1 mAb in a mouse model of prostate cancer. Cancer Immunol Immunother 2016; 65:701-13. [PMID: 27052571 PMCID: PMC4880633 DOI: 10.1007/s00262-016-1831-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 03/22/2016] [Indexed: 11/06/2022]
Abstract
Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime–boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), induced strong sustained antigen-specific CD8+ T-cell responses in C57BL/6 and BALB/c male mice. Unexpectedly, the high vaccine immunogenicity translated into relatively low protective efficacy in the murine transplantable and spontaneous models of prostate cancer. A combination of the vaccine with PD-1 blocking antibody significantly improved survival of the animals, with 80 % of mice remaining tumour-free. These results indicate that the ChAdOx1–MVA vaccination regime targeting STEAP1 combined with PD-1 therapy might have high therapeutic potential in the clinic.
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Anti-tumor effect of the alphavirus-based virus-like particle vector expressing prostate-specific antigen in a HLA-DR transgenic mouse model of prostate cancer. Vaccine 2015; 33:5386-5395. [PMID: 26319744 DOI: 10.1016/j.vaccine.2015.08.062] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 06/23/2015] [Accepted: 08/18/2015] [Indexed: 12/21/2022]
Abstract
The goal of this study was to determine if an alphavirus-based vaccine encoding human Prostate-Specific Antigen (PSA) could generate an effective anti-tumor immune response in a stringent mouse model of prostate cancer. DR2bxPSA F1 male mice expressing human PSA and HLA-DRB1(*)1501 transgenes were vaccinated with virus-like particle vector encoding PSA (VLPV-PSA) followed by the challenge with Transgenic Adenocarcinoma of Mouse Prostate cells engineered to express PSA (TRAMP-PSA). PSA-specific cellular and humoral immune responses were measured before and after tumor challenge. PSA and CD8 reactivity in the tumors was detected by immunohistochemistry. Tumor growth was compared in vaccinated and control groups. We found that VLPV-PSA could infect mouse dendritic cells in vitro and induce a robust PSA-specific immune response in vivo. A substantial proportion of splenic CD8 T cells (19.6 ± 7.4%) produced IFNγ in response to the immunodominant peptide PSA(65-73). In the blood of vaccinated mice, 18.4 ± 4.1% of CD8 T cells were PSA-specific as determined by the staining with H-2D(b)/PSA(65-73) dextramers. VLPV-PSA vaccination also strongly stimulated production of IgG2a/b anti-PSA antibodies. Tumors in vaccinated mice showed low levels of PSA expression and significant CD8+ T cell infiltration. Tumor growth in VLPV-PSA vaccinated mice was significantly delayed at early time points (p=0.002, Gehan-Breslow test). Our data suggest that TC-83-based VLPV-PSA vaccine can efficiently overcome immune tolerance to PSA, mediate rapid clearance of PSA-expressing tumor cells and delay tumor growth. The VLPV-PSA vaccine will undergo further testing for the immunotherapy of prostate cancer.
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40
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Lundstrom K. Alphavirus vectors as tools in neuroscience and gene therapy. Virus Res 2015; 216:16-25. [PMID: 26307195 DOI: 10.1016/j.virusres.2015.08.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/17/2015] [Accepted: 08/19/2015] [Indexed: 11/30/2022]
Abstract
Alphavirus-based vectors have been engineered for in vitro and in vivo expression of heterelogous genes. The rapid and easy generation of replication-deficient recombinant particles and the broad range of host cell infection have made alphaviruses attractive vehicles for applications in neuroscience and gene therapy. Efficient delivery to primary neurons and hippocampal slices has allowed localization studies of gene expression and electrophysiological recordings of ion channels. Alphavirus vectors have also been applied for in vivo delivery to rodent brain. Due to the strong local transient expression provided by alphavirus vectors a number of immunization and gene therapy approaches have demonstrated both therapeutic and prophylactic efficacy in various animal models.
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41
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Cole G, McCaffrey J, Ali AA, McCarthy HO. DNA vaccination for prostate cancer: key concepts and considerations. Cancer Nanotechnol 2015; 6:2. [PMID: 26161151 PMCID: PMC4488504 DOI: 10.1186/s12645-015-0010-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 05/16/2015] [Indexed: 11/10/2022] Open
Abstract
While locally confined prostate cancer is associated with a low five year mortality rate, advanced or metastatic disease remains a major challenge for healthcare professionals to treat and is usually terminal. As such, there is a need for the development of new, efficacious therapies for prostate cancer. Immunotherapy represents a promising approach where the host's immune system is harnessed to mount an anti-tumour effect, and the licensing of the first prostate cancer specific immunotherapy in 2010 has opened the door for other immunotherapies to gain regulatory approval. Among these strategies DNA vaccines are an attractive option in terms of their ability to elicit a highly specific, potent and wide-sweeping immune response. Several DNA vaccines have been tested for prostate cancer and while they have demonstrated a good safety profile they have faced problems with low efficacy and immunogenicity compared to other immunotherapeutic approaches. This review focuses on the positive aspects of DNA vaccines for prostate cancer that have been assessed in preclinical and clinical trials thus far and examines the key considerations that must be employed to improve the efficacy and immunogenicity of these vaccines.
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Affiliation(s)
- Grace Cole
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland UK
| | - Joanne McCaffrey
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland UK
| | - Ahlam A Ali
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland UK
| | - Helen O McCarthy
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland UK
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42
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Cho HI, Jung SH, Sohn HJ, Celis E, Kim TG. An optimized peptide vaccine strategy capable of inducing multivalent CD8 + T cell responses with potent antitumor effects. Oncoimmunology 2015; 4:e1043504. [PMID: 26451316 PMCID: PMC4589052 DOI: 10.1080/2162402x.2015.1043504] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 04/14/2015] [Accepted: 04/16/2015] [Indexed: 12/19/2022] Open
Abstract
Therapeutic cancer vaccines are an attractive alternative to conventional therapies for treating malignant tumors, and successful tumor eradication depends primarily on obtaining high numbers of long-lasting tumor-reactive CD8+ T cells. Dendritic cell (DC)-based vaccines constitute a promising approach for treating cancer, but in most instances low immune responses and suboptimal therapeutic effects are achieved indicating that further optimization is required. We describe here a novel vaccination strategy with peptide-loaded DCs followed by a mixture of synthetic peptides, polyinosine-polycytidylic acid (poly-IC) and anti-CD40 antibodies (TriVax) for improving the immunogenicity and therapeutic efficacy of DC-based vaccines in a melanoma mouse model. TriVax immunization 7–12 d after priming with antigen-loaded DCs generated large numbers of long-lasting multiple antigen-specific CD8+ T cells capable of recognizing tumor cells. These responses were far superior to those generated by homologous immunizations with either TriVax or DCs. CD8+ T cells but not CD4+ T cells or NK cells mediated the therapeutic efficacy of this heterologous prime-boost strategy. Moreover, combinations of this vaccination regimen with programmed cell death-1 (PD-1) blockade or IL2 anti-IL2 antibody complexes led to complete disease eradication and survival enhancement in melanoma-bearing mice. The overall results suggest that similar strategies would be applicable for the design of effective therapeutic vaccination for treating viral diseases and various cancers, which may circumvent current limitations of cell-based cancer vaccines.
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Affiliation(s)
- Hyun-Il Cho
- Catholic Hematopoietic Stem Cell Bank; College of Medicine; The Catholic University of Korea ; Seoul, Korea ; Cancer Research Institute; College of Medicine; The Catholic University of Korea ; Seoul, Korea
| | - Soo-Hyun Jung
- Catholic Hematopoietic Stem Cell Bank; College of Medicine; The Catholic University of Korea ; Seoul, Korea ; Cancer Research Institute; College of Medicine; The Catholic University of Korea ; Seoul, Korea
| | - Hyun-Jung Sohn
- Catholic Hematopoietic Stem Cell Bank; College of Medicine; The Catholic University of Korea ; Seoul, Korea
| | - Esteban Celis
- Cancer Immunology; Inflammation and Tolerance Program; Georgia Regents University Cancer Center ; Augusta, GA USA
| | - Tai-Gyu Kim
- Catholic Hematopoietic Stem Cell Bank; College of Medicine; The Catholic University of Korea ; Seoul, Korea ; Cancer Research Institute; College of Medicine; The Catholic University of Korea ; Seoul, Korea ; College of Medicine; The Catholic University of Korea ; Seoul, South Korea
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43
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Zhuang X, Herbert JMJ, Lodhia P, Bradford J, Turner AM, Newby PM, Thickett D, Naidu U, Blakey D, Barry S, Cross DAE, Bicknell R. Identification of novel vascular targets in lung cancer. Br J Cancer 2015; 112:485-94. [PMID: 25535734 PMCID: PMC4453649 DOI: 10.1038/bjc.2014.626] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/13/2014] [Accepted: 11/26/2014] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. METHODS Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology. RESULTS Bioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation. CONCLUSIONS The identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development.
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MESH Headings
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Non-Small-Cell Lung/blood supply
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Female
- Gene Expression Profiling
- Genetic Association Studies/methods
- Humans
- Lung/blood supply
- Lung/metabolism
- Lung/pathology
- Lung Neoplasms/blood supply
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Male
- Microarray Analysis
- Middle Aged
- Molecular Targeted Therapy
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Real-Time Polymerase Chain Reaction
- Sequence Analysis, RNA
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Affiliation(s)
- X Zhuang
- School of Immunity and Infection,
Institute for Biomedical Research, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham
B15 2TT, UK
- School of Cancer Sciences, College of
Medical and Dental Sciences, University of Birmingham,
Edgbaston, Birmingham
B15 2TT, UK
| | - J M J Herbert
- School of Immunity and Infection,
Institute for Biomedical Research, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham
B15 2TT, UK
- Technology Hub Sequencing and
Bioinformatics, College of Medical and Dental Sciences,
Birmingham
B15, UK
| | - P Lodhia
- School of Immunity and Infection,
Institute for Biomedical Research, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham
B15 2TT, UK
| | - J Bradford
- AstraZeneca, Mereside,
Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK
| | - A M Turner
- School of Clinical and Experimental
Medicine, University of Birmingham, QEHB Research Laboratories,
Mindelsohn Way, Birmingham
B15 2WB, UK
- Birmingham Heartlands Hospital,
Bordesley Green, Birmingham
B9 5SS, UK
| | - P M Newby
- School of Immunity and Infection,
Institute for Biomedical Research, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham
B15 2TT, UK
| | - D Thickett
- School of Clinical and Experimental
Medicine, University of Birmingham, QEHB Research Laboratories,
Mindelsohn Way, Birmingham
B15 2WB, UK
| | - U Naidu
- School of Clinical and Experimental
Medicine, University of Birmingham, QEHB Research Laboratories,
Mindelsohn Way, Birmingham
B15 2WB, UK
- Birmingham Heartlands Hospital,
Bordesley Green, Birmingham
B9 5SS, UK
| | - D Blakey
- AstraZeneca, Mereside,
Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK
| | - S Barry
- AstraZeneca, Mereside,
Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK
| | - D A E Cross
- AstraZeneca, Mereside,
Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK
| | - R Bicknell
- School of Immunity and Infection,
Institute for Biomedical Research, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham
B15 2TT, UK
- School of Cancer Sciences, College of
Medical and Dental Sciences, University of Birmingham,
Edgbaston, Birmingham
B15 2TT, UK
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44
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Abstract
RNA-based approaches have provided novel alternatives for modern drug discovery. The application of RNA as therapeutic agents has, until recently, been hampered by issues related to poor delivery and stability, but chemical modifications and new delivery approaches have increased progress. Moreover, the discovery of the importance of RNA in gene regulation and gene silencing has revealed new drug targets, especially related to treatment of cancer and other diseases. Recent engineering of small molecules designed from RNA sequences to target miRNAs opens up new possibilities in drug development. Furthermore, RNA-based vaccines have been engineered applying RNA virus vectors and non-viral delivery for vaccine development.
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45
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Expression of STEAP1 and STEAP1B in prostate cell lines, and the putative regulation of STEAP1 by post-transcriptional and post-translational mechanisms. Genes Cancer 2014; 5:142-51. [PMID: 25053991 PMCID: PMC4091532 DOI: 10.18632/genesandcancer.13] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 06/10/2014] [Indexed: 12/26/2022] Open
Abstract
STEAP1 gene is overexpressed in several kinds of tumors, particularly in prostate cancer. Besides STEAP1, there is another related gene, STEAP1B, which may encode two different transcripts. Although several studies have been pointing STEAP1 as a putative immunotherapeutic target and biomarker, the mechanisms underlying its regulation are not fully understood. In silico analysis allowed us to show that STEAP1 and STEAP1B share high homology, but with slight differences at structural level. Experiments with prostate cells showed that STEAP1B2 is overexpressed in cancer cells. Regarding STEAP1 regulation, it is demonstrated that the stability of mRNA and protein is higher in LNCaP than in PNT1A cells. Of note, serum triggered opposite effects in LNCaP and PNT1A in relation to STEAP1 stability, e.g., increasing it in PNT1A and decreasing in LNCaP. These results suggest that STEAP1 may be regulated by post-transcriptional and post-translational modifications (PTM), which may differ between non-neoplastic and neoplastic cells. These PTM are supported through in silico analysis, where several modifications such as N-glycosylation, N-Glycation, Phosphorylation and O-linked β-N-acetylglucosamine, may occur in STEAP1 protein. In conclusion, these data indicate that STEAP1B2 is overexpressed in neoplastic cells, and PTM may be involved in regulation of STEAP1 expression in prostate cells.
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46
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Alphavirus-based vaccines. Viruses 2014; 6:2392-415. [PMID: 24937089 PMCID: PMC4074933 DOI: 10.3390/v6062392] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 06/03/2014] [Accepted: 06/04/2014] [Indexed: 12/18/2022] Open
Abstract
Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against alphaviruses themselves. Recent progress in alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.
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47
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Xiang SD, Scalzo-Inguanti K, Minigo G, Park A, Hardy CL, Plebanski M. Promising particle-based vaccines in cancer therapy. Expert Rev Vaccines 2014; 7:1103-19. [DOI: 10.1586/14760584.7.7.1103] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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48
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WANG YUQIAN, LIU CHENLU, XIA QIU, WANG PENG, LI BO, LU ZHENZHEN, SUN JIAXI, WU HUI, YU BIN, WU JIAXIN, YU XIANGHUI, KONG WEI, ZHANG HAIHONG, CONG XIANLING. Antitumor effect of adenoviral vector prime protein boost immunity targeting the MUC1 VNTRs. Oncol Rep 2013; 31:1437-44. [DOI: 10.3892/or.2013.2950] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 12/09/2013] [Indexed: 11/06/2022] Open
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49
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Colluru VT, Johnson LE, Olson BM, McNeel DG. Preclinical and clinical development of DNA vaccines for prostate cancer. Urol Oncol 2013; 34:193-204. [PMID: 24332642 DOI: 10.1016/j.urolonc.2013.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/12/2013] [Accepted: 09/13/2013] [Indexed: 11/26/2022]
Abstract
Prostate cancer is the most commonly diagnosed cancer in the United States. It is also the second leading cause of cancer-related death in men, making it one of the largest public health concerns today. Prostate cancer is an ideal disease for immunotherapies because of the generally slow progression, the dispensability of the target organ in the patient population, and the availability of several tissue-specific antigens. As such, several therapeutic vaccines have entered clinical trials, with one autologous cellular vaccine (sipuleucel-T) recently gaining Food and Drug Administration approval after demonstrating overall survival benefit in randomized phase III clinical trials. DNA-based vaccines are safe, economical, alternative "off-the-shelf" approaches that have undergone extensive evaluation in preclinical models. In fact, the first vaccine approved in the United States for the treatment of cancer was a DNA vaccine for canine melanoma. Several prostate cancer-specific DNA vaccines have been developed in the last decade and have shown promising results in early phase clinical trials. This review summarizes anticancer human DNA vaccine trials, with a focus on those conducted for prostate cancer. We conclude with an outline of special considerations important for the development and successful translation of DNA vaccines from the laboratory to the clinic.
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Affiliation(s)
- V T Colluru
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI
| | - Laura E Johnson
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI
| | - Brian M Olson
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI
| | - Douglas G McNeel
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI.
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50
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Ihlaseh-Catalano SM, Drigo SA, de Jesus CMN, Domingues MAC, Trindade Filho JCS, de Camargo JLV, Rogatto SR. STEAP1 protein overexpression is an independent marker for biochemical recurrence in prostate carcinoma. Histopathology 2013; 63:678-85. [PMID: 24025158 DOI: 10.1111/his.12226] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 07/11/2013] [Indexed: 12/22/2022]
Abstract
AIMS To investigate the prognostic value of expression levels of the genes STEAP1 and STEAP2, and of STEAP1 protein, in prostate carcinomas (PCa). METHODS AND RESULTS STEAP1 and STEAP2 transcript levels were evaluated by RT-qPCR in samples from 35 PCa, 24 adjacent non-neoplastic prostate (AdjP) tissues, five cases of benign prostatic hyperplasia (BPH), and two histologically normal prostates (N). STEAP1 expression was assessed by immunohistochemistry in samples from 198 PCa, 76 AdjP, 22 BPH, and two N. The findings were compared with clinical and pathological parameters and patient outcome. STEAP1 and STEAP2 transcript analysis showed no differences between the groups tested. Although not significant, higher STEAP1 mRNA levels were detected in tumours with high Gleason scores and in patients who presented with biochemical recurrence (BCR). STEAP1 overexpression was detected in PCa, and was significantly associated with high-grade Gleason scores, seminal vesicle invasion, BCR, and worse outcome (metastasis or PCa-specific death). STEAP1 overexpression was significantly associated with shorter BCR-free survival. Multivariate analysis revealed that STEAP1 is an independent marker for BCR. CONCLUSIONS These findings provide evidence that STEAP1 is a biomarker of worse prognosis in PCa patients.
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