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1
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Lo J, Kung CC, Cheng TJR, Wong CH, Ma C. Structure-Based Mechanism and Specificity of Human Galactosyltransferase β3GalT5. J Am Chem Soc 2025; 147:10875-10885. [PMID: 40130308 PMCID: PMC11969544 DOI: 10.1021/jacs.4c11724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 03/26/2025]
Abstract
Human β1,3-galactosyltransferase 5 (β3GalT5) is a key enzyme involved in the synthesis of glycans on glycoproteins and glycolipids that are associated with various important biological functions, especially tumor malignancy and cancer progression, and has been considered as a promising target for development of anticancer agents. In this study, we determined the X-ray structures of β3GalT5 in complex with the stable donor analogue UDP-2-fluorogalactose or the native donor substrate UDP-galactose (UDP-Gal) and several glycan acceptors at different reaction steps. Based on the structures obtained from our experiments, β3GalT5 catalyzes the transfer of galactose from UDP-Gal to a broad spectrum of glycan acceptors with an SN2-like mechanism; however, in the absence of a glycan acceptor, UDP-Gal is slowly converted to UDP and two other products, one is galactose through an SN2-like mechanism with water as an acceptor and the other is an oxocarbenium-like product, presumably through an SN1-like mechanisms. The structure, mechanism, and specificity of β3GalT5 presented in this study advance our understanding of enzymatic glycosylation and provide valuable insights for application to glycan synthesis and drug design targeting β3GalT5-associated cancer.
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Affiliation(s)
- Jennifer
M. Lo
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Chemical
Biology and Molecular Biophysics Program, Taiwan International Graduate
Program, Academia Sinica, Taipei 115, Taiwan
- Department
of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Chih-Chuan Kung
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
| | | | - Chi-Huey Wong
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Department
of Chemistry, Scripps Research, La Jolla, California 92037, United States
| | - Che Ma
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Chemical
Biology and Molecular Biophysics Program, Taiwan International Graduate
Program, Academia Sinica, Taipei 115, Taiwan
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2
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Kung CC, Lo JM, Liao KS, Wu CY, Cheng LC, Chung C, Hsu TL, Ma C, Wong CH. Expression of Human β3GalT5-1 in Insect Cells as Active Glycoforms for the Efficient Synthesis of Cancer-Associated Globo-Series Glycans. J Am Chem Soc 2025; 147:10864-10874. [PMID: 40130300 PMCID: PMC11969553 DOI: 10.1021/jacs.4c11723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 01/13/2025] [Accepted: 02/05/2025] [Indexed: 03/26/2025]
Abstract
The globo-series glycosphingolipids (GSLs) are unique glycolipids exclusively expressed on the cell surface of various types of cancer and have been used as targets for the development of cancer vaccines and therapeutics. A practical enzymatic method has been developed for the synthesis of globo-series glycans, where the conversion of Gb4 to Gb5 (SSEA-3) glycan based on the microbial galactosyltransferase LgtD is relatively inefficient compared to other steps. To improve the efficiency, we explored the two human galactosyltransferase (β3GalT5) isozymes in cancer cells for this reaction and found that isozyme 1 (β3GalT5-1) is more active than isozyme 2 (β3GalT5-2). We then identified a common soluble domain of the two β3GalT5 isozymes as a candidate and evaluated the activity and substrate specificity of the glycosylated and nonglycosylated glycoforms. The glycoforms expressed in Sf9 cells were selected, and a site-specific alanine scan was performed to identify S66A β3GalT5 variant with 10-fold more efficiency than LgtD for the synthesis of globo-series glycans. The X-ray structure of β3GalT5-1 was determined for molecular modeling, and the result together with kinetic data were used to rationalize the improvement in catalysis.
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Affiliation(s)
- Chih-Chuan Kung
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Jennifer M. Lo
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Kuo-Shiang Liao
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Chung-Yi Wu
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Li-Chun Cheng
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Cinya Chung
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Tsui-Ling Hsu
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Che Ma
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Chi-Huey Wong
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
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3
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Pousa S, Ramos-Bermúdez PE, Besada V, Cabrales-Rico A, Guirola Cruz O, Garay HE, Rodríguez-Mallón A, Zettl K, Wiśniewski JR, González LJ. Characterization by LC-MS/MS analysis of KLH vaccine conjugated with a tick antigen peptide. Analyst 2025; 150:1091-1102. [PMID: 39817672 DOI: 10.1039/d4an01449a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
Keyhole limpet haemocyanins (KLH1 and KLH2) from Megathura crenulata, are multi-subunit oxygen-carrying metalloproteins of approximately 3900 amino acids, that are widely used as carrier proteins in conjugate vaccines and in immunotherapy. KLHs and their derived conjugate vaccines are poorly characterized by LC-MS/MS due to their very stable supramolecular structures with megadalton molecular mass, and their resistance to efficient digestion with standard protocols. KLH1 and KLH2 proteins were conjugated to the conserved P0 peptide (pP0), derived from the P0 acidic ribosomal protein of Rhipicephalus sp. ticks using maleimide-thiol chemistry to obtain a broad-spectrum anti-tick vaccine. The resulting KLH1- and KLH2-Cys1pP0 conjugate vaccines were efficiently digested using the Multiple-Enzymatic Digestion Filter Aided Sample Preparation and analyzed by LC-MS/MS, enabling a sequence coverage of approximately 85% of both conjugates. Seventy-three and sixty-five percent of all lysine residues in KLH1 and KLH2, respectively, were partially conjugated to Cys1pP0. In the quaternary structures, we found no bias toward conjugation of lysine residues exposed to either the outer surface or the inner channel. The latter may not contribute to a protective humoral response because B cell entry into the inner channel is incompatible with the entrance hole diameter. The Cys-His thioether bonds in both KLHs were determined by identifying type 1 cross-linked peptides. New post-translational modifications undescribed for the KLH such as oxidized species, were identified. This is the first report of the identification of conjugation sites of two KLH-based vaccines. These results will help translate the KLH-based conjugates into well-characterized biotechnology products.
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Affiliation(s)
- Satomy Pousa
- Department of Proteomics, Mass Spectrometry Laboratory, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba.
| | - Pablo E Ramos-Bermúdez
- Bioinformatics, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba
| | - Vladimir Besada
- Department of Proteomics, Mass Spectrometry Laboratory, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba.
| | - Ania Cabrales-Rico
- Purification and Analytic Group, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba
| | - Osmany Guirola Cruz
- Bioinformatics, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba
| | - Hilda Elisa Garay
- Laboratory of Peptide Synthesis, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba
| | - Alina Rodríguez-Mallón
- Animal Biotechnology, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba
| | - Katharina Zettl
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Munich, Germany
| | - Jacek R Wiśniewski
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Munich, Germany
| | - Luis Javier González
- Department of Proteomics, Mass Spectrometry Laboratory, Center for Genetic Engineering and Biotechnology, 31 Avenue, Cubanacan, Playa, Havana, Cuba.
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4
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Rodriguez E. Tumor Glycosylation: A Main Player in the Modulation of Immune Responses. Eur J Immunol 2025; 55:e202451318. [PMID: 40071681 PMCID: PMC11898543 DOI: 10.1002/eji.202451318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 02/13/2025] [Accepted: 02/17/2025] [Indexed: 03/15/2025]
Abstract
Tumor immune escape refers to the process by which cancer cells evade detection and destruction by the immune system. Glycosylation, a post-translational modification that is altered in almost all cancer types, plays a crucial role in this process by modulating immune responses. This review examines our current understanding of how aberrant tumor glycosylation contributes to a tolerogenic microenvironment, focusing on specific glycosylation signatures-fucosylation, truncated O-glycans, and sialylation-and the immune receptors involved. Additionally, the clinical significance of tumor glycosylation is discussed, emphasizing its potential in developing novel therapeutic approaches aimed at improving immune system recognition and targeting of cancer cells. The review underscores the importance of ongoing research in this area to identify effective strategies for countering tumor immune escape and enhancing the efficacy of cancer treatments.
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Affiliation(s)
- Ernesto Rodriguez
- Amsterdam UMC location Vrije Universiteit AmsterdamMolecular Cell Biology and ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Biology and ImmunologyAmsterdamThe Netherlands
- Amsterdam Institute for Infection and ImmunityCancer ImmunologyAmsterdamThe Netherlands
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5
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Xu L, Xu P, Wang J, Ji H, Zhang L, Tang Z. Advancements in clinical research and emerging therapies for triple-negative breast cancer treatment. Eur J Pharmacol 2025; 988:177202. [PMID: 39675457 DOI: 10.1016/j.ejphar.2024.177202] [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: 08/02/2024] [Revised: 11/30/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%-20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community. This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.
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Affiliation(s)
- Lili Xu
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Pengtao Xu
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Jingsong Wang
- Department of Pharmacy, Guangyuan Central Hospital, Guangyuan, Sichuan, 628000, China
| | - Hui Ji
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Zhihua Tang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China.
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6
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Heater NK, Warrior S, Lu J. Current and future immunotherapy for breast cancer. J Hematol Oncol 2024; 17:131. [PMID: 39722028 PMCID: PMC11670461 DOI: 10.1186/s13045-024-01649-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
Substantial therapeutic advancement has been made in the field of immunotherapy in breast cancer. The immune checkpoint inhibitor pembrolizumab in combination with chemotherapy received FDA approval for both PD-L1 positive metastatic and early-stage triple-negative breast cancer, while ongoing clinical trials seek to expand the current treatment landscape for immune checkpoint inhibitors in hormone receptor positive and HER2 positive breast cancer. Antibody drug conjugates are FDA approved for triple negative and HER2+ disease, and are being studied in combination with immune checkpoint inhibitors. Vaccines and bispecific antibodies are areas of active research. Studies of cellular therapies such as tumor infiltrating lymphocytes, chimeric antigen receptor-T cells and T cell receptor engineered cells are promising and ongoing. This review provides an update of recent major clinical trials of immunotherapy in breast cancer and discusses future directions in the treatment of breast cancer.
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Affiliation(s)
- Natalie K Heater
- Department of Medicine, McGaw Medical Center of Northwestern University, Chicago, IL, 60611, USA
| | - Surbhi Warrior
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 N St. Clair, Suite 850, Chicago, IL, 60611, USA
| | - Janice Lu
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 N St. Clair, Suite 850, Chicago, IL, 60611, USA.
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7
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Liu T, Yao W, Sun W, Yuan Y, Liu C, Liu X, Wang X, Jiang H. Components, Formulations, Deliveries, and Combinations of Tumor Vaccines. ACS NANO 2024; 18:18801-18833. [PMID: 38979917 DOI: 10.1021/acsnano.4c05065] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating or restoring the body's own immune system. Currently, various formulations of tumor vaccines have been developed, including cell vaccines, tumor cell membrane vaccines, tumor DNA vaccines, tumor mRNA vaccines, tumor polypeptide vaccines, virus-vectored tumor vaccines, and tumor-in-situ vaccines. There are also multiple delivery systems for tumor vaccines, such as liposomes, cell membrane vesicles, viruses, exosomes, and emulsions. In addition, to decrease the risk of tumor immune escape and immune tolerance that may exist with a single tumor vaccine, combination therapy of tumor vaccines with radiotherapy, chemotherapy, immune checkpoint inhibitors, cytokines, CAR-T therapy, or photoimmunotherapy is an effective strategy. Given the critical role of tumor vaccines in immunotherapy, here, we look back to the history of tumor vaccines, and we discuss the antigens, adjuvants, formulations, delivery systems, mechanisms, combination therapy, and future directions of tumor vaccines.
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Affiliation(s)
- Tengfei Liu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Wenyan Yao
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Wenyu Sun
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Yihan Yuan
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Chen Liu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Xiaohui Liu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Xuemei Wang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Hui Jiang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
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8
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Hung TH, Huang Y, Yeh CT, Yeh CN, Yu J, Lin CC, Chiou SP, Chiang PY, Hung JT, Yu AL. High expression of embryonic stem cell marker SSEA3 confers poor prognosis and promotes epithelial mesenchymal transition in hepatocellular carcinoma. Biomed J 2024; 47:100612. [PMID: 37290529 PMCID: PMC10972813 DOI: 10.1016/j.bj.2023.100612] [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: 12/13/2022] [Revised: 04/26/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023] Open
Abstract
BACKGROUND Malignant cells may arise from dedifferentiation of mature cells and acquire features of the progenitor cells. Definitive endoderm from which liver is derived, expresses glycosphingolipids (GSLs) such as stage-specific embryonic antigen 3 (SSEA3), Globo H, and stage-specific embryonic antigen 4 (SSEA4). Herein, we evaluated the potential prognosis value of the three GSLs and biological functions of SSEA3 in hepatocellular carcinoma (HCC). METHODS The expression of SSEA3, Globo H, and SSEA4 in tumor tissues obtained from 328 patients with resectable HCC was examined by immunohistochemistry staining. Epithelial mesenchymal transition (EMT) and their related genes were analyzed by transwell assay and qRT-PCR, respectively. RESULTS Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with higher expression of SSEA3 (p < 0.001), Globo H (p < 0.001), and SSEA4 (p = 0.005) and worse overall survival (OS) for those with high expression of either SSEA3 (p < 0.001) or SSEA4 (p = 0.01). Furthermore, multivariable Cox regression analysis identified the SSEA3 as an independent predictor for RFS (HR: 2.68, 95% CI: 1.93-3.72, p < 0.001) and OS (HR: 2.99, 95% CI: 1.81-4.96, p < 0.001) in HCC. Additionally, SSEA3-ceramide enhanced the EMT of HCC cells, as reflected by its ability to increase migration, invasion and upregulate the expression of CDH2, vimentin, fibronectin, and MMP2, along with ZEB1. Moreover, ZEB1 silencing abrogated the EMT-enhancing effects of SSEA3-ceramide. CONCLUSIONS Higher expression of SSEA3 was an independent predictor for RFS and OS in HCC and promoted EMT of HCC via upregulation of ZEB1.
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Affiliation(s)
- Tsai-Hsien Hung
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yenlin Huang
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linko, Taoyuan, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - John Yu
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Cheng Lin
- Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
| | - Shih-Pin Chiou
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Pei-Yun Chiang
- Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
| | - Alice L Yu
- Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, University of California in San Diego, San Diego, CA, USA.
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9
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Rashidijahanabad Z, Ramadan S, O'Brien NA, Nakisa A, Lang S, Crawford H, Gildersleeve JC, Huang X. Stereoselective Synthesis of Sialyl Lewis a Antigen and the Effective Anticancer Activity of Its Bacteriophage Qβ Conjugate as an Anticancer Vaccine. Angew Chem Int Ed Engl 2023; 62:e202309744. [PMID: 37781858 PMCID: PMC10842512 DOI: 10.1002/anie.202309744,] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Indexed: 06/15/2024]
Abstract
Sialyl Lewisa (sLea ), also known as cancer antigen 19-9 (CA19-9), is a tumor-associated carbohydrate antigen. The overexpression of sLea on the surface of a variety of cancer cells makes it an attractive target for anticancer immunotherapy. However, sLea -based anticancer vaccines have been under-explored. To develop a new vaccine, efficient stereoselective synthesis of sLea with an amine-bearing linker was achieved, which was subsequently conjugated with a powerful carrier bacteriophage, Qβ. Mouse immunization with the Qβ-sLea conjugate generated strong and long-lasting anti-sLea IgG antibody responses, which were superior to those induced by the corresponding conjugate of sLea with the benchmark carrier keyhole limpet hemocyanin. Antibodies elicited by Qβ-sLea were highly selective toward the sLea structure, could bind strongly with sLea -expressing cancer cells and human pancreatic cancer tissues, and kill tumor cells through complement-mediated cytotoxicity. Furthermore, vaccination with Qβ-sLea significantly reduced tumor development in a metastatic cancer model in mice, demonstrating tumor protection for the first time by a sLea -based vaccine, thus highlighting the significant potential of sLea as a promising cancer antigen.
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Affiliation(s)
- Zahra Rashidijahanabad
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Sherif Ramadan
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
- Chemistry Department, Faculty of Science, Benha University, 13518, Benha, Qaliobiya, Egypt
| | - Nicholas A O'Brien
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, 21702, USA
| | - Athar Nakisa
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Shuyao Lang
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Howard Crawford
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, 48202, USA
| | - Jeffrey C Gildersleeve
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, 21702, USA
| | - Xuefei Huang
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
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10
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Rashidijahanabad Z, Ramadan S, O'Brien NA, Nakisa A, Lang S, Crawford H, Gildersleeve JC, Huang X. Stereoselective Synthesis of Sialyl Lewis a Antigen and the Effective Anticancer Activity of Its Bacteriophage Qβ Conjugate as an Anticancer Vaccine. Angew Chem Int Ed Engl 2023; 62:e202309744. [PMID: 37781858 PMCID: PMC10842512 DOI: 10.1002/anie.202309744] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/23/2023] [Accepted: 09/27/2023] [Indexed: 10/03/2023]
Abstract
Sialyl Lewisa (sLea ), also known as cancer antigen 19-9 (CA19-9), is a tumor-associated carbohydrate antigen. The overexpression of sLea on the surface of a variety of cancer cells makes it an attractive target for anticancer immunotherapy. However, sLea -based anticancer vaccines have been under-explored. To develop a new vaccine, efficient stereoselective synthesis of sLea with an amine-bearing linker was achieved, which was subsequently conjugated with a powerful carrier bacteriophage, Qβ. Mouse immunization with the Qβ-sLea conjugate generated strong and long-lasting anti-sLea IgG antibody responses, which were superior to those induced by the corresponding conjugate of sLea with the benchmark carrier keyhole limpet hemocyanin. Antibodies elicited by Qβ-sLea were highly selective toward the sLea structure, could bind strongly with sLea -expressing cancer cells and human pancreatic cancer tissues, and kill tumor cells through complement-mediated cytotoxicity. Furthermore, vaccination with Qβ-sLea significantly reduced tumor development in a metastatic cancer model in mice, demonstrating tumor protection for the first time by a sLea -based vaccine, thus highlighting the significant potential of sLea as a promising cancer antigen.
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Affiliation(s)
- Zahra Rashidijahanabad
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Sherif Ramadan
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
- Chemistry Department, Faculty of Science, Benha University, 13518, Benha, Qaliobiya, Egypt
| | - Nicholas A O'Brien
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, 21702, USA
| | - Athar Nakisa
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Shuyao Lang
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
| | - Howard Crawford
- Department of Surgery, Henry Ford Health System, Detroit, Michigan, 48202, USA
| | - Jeffrey C Gildersleeve
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, 21702, USA
| | - Xuefei Huang
- Department of Chemistry, Michigan State University, 48824, East Lansing, Michigan, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, 48824, East Lansing, Michigan, USA
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11
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Hung TH, Yeh CN, Hung JT, Wu CE, Lee CW, Yu J, Yu AL, Huang Y. Globo H ceramide is an independent prognostic marker for gallbladder cancer. Am J Cancer Res 2023; 13:4811-4821. [PMID: 37970342 PMCID: PMC10636676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/23/2023] [Indexed: 11/17/2023] Open
Abstract
In recent studies, there has been growing interest in developing cancer therapeutics targeting Globo H ceramide, which is considered as the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. In this study, we aimed to evaluate the expression of Globo H and investigate its prognostic significance in gallbladder cancer (GBC). The tumor specimens and clinical characteristics of GBC patients were collected from the tumor bank and database of Chang Gung Memorial Hospital. Globo H in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry analysis. Through data mining, it was discovered that FUT1 and FUT2, which are key enzymes involved in the biosynthesis of Globo H, were significantly up-regulated in human gallbladder cancer (GBC). Consistent with this finding, Globo H expression was detected in 86% (128 out of 149) of GBC specimens using immunohistochemical (IHC) staining. This was the highest frequency among Globo H expressing cancers. Patients with tumors exhibiting higher Globo H expression (H-score ≥ 80) demonstrated significantly shorter disease-free survival (DFS) and overall survival (OS) (P = 0.0001 and P = 0.0004, respectively). In a multivariable Cox regression analysis, elevated Globo H expression was identified as an independent unfavorable predictor for DFS and OS (hazard ratio: 2.29 and 2.32, respectively, P = 0.008 and 0.001) in primary GBC. Globo H is an independent prognostic marker for GBC.
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Affiliation(s)
- Tsai-Hsien Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
| | - Chiao-En Wu
- Department of Hematology-Oncology, Chang Gung Memorial Hospital, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Chien-Wei Lee
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
- Chang Gung UniversityTaoyuan 333, Taiwan
| | - Alice L. Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
- Chang Gung UniversityTaoyuan 333, Taiwan
- Department of Pediatrics, University of California in San DiegoSan Diego, CA 92103, USA
| | - Yenlin Huang
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
- School of Medicine, National Tsing Hua UniversityHsinchu 300, Taiwan
- Department of Anatomic Pathology, Chang Gung Memorial Hospital at LinkouTaoyuan 333, Taiwan
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12
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FAN H, GE X, ZHOU X, LI Y, WANG A, HU Y. [Research Progress of Lung Cancer Vaccines]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2023; 26:692-700. [PMID: 37985155 PMCID: PMC10600751 DOI: 10.3779/j.issn.1009-3419.2023.106.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Indexed: 11/22/2023]
Abstract
With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines.
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13
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Hsu HT, Kuo TM, Wei CY, Huang JY, Liu TW, Hsing MT, Lai MT, Chen CT. Investigation of the impact of Globo-H expression on the progression of gastric cancer. Am J Cancer Res 2023; 13:2969-2983. [PMID: 37560002 PMCID: PMC10408484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 05/28/2023] [Indexed: 08/11/2023] Open
Abstract
Globo-H (GH), a globo-series glycosphingolipid antigen that is synthesized by key enzymes β1,3-galactosyltransferase V (β3GalT5), fucosyltransferase (FUT) 1 and 2, is highly expressed on a variety of epithelial cancers rendering it a promising target for cancer immunotherapy. GH-targeting antibody-drug conjugate has been demonstrated an excellent tumor growth inhibition potency in animal models across multiple cancer types including Gastric cancer (GC). This study aims to further investigate the GH roles in GC. Significant correlations were observed between high mRNA expression of GH-synthetic key enzymes and worse overall survival (OS)/post-progression survival for GC patients based on the data from "Kaplan-Meier plotter" database (n=498). The level of GH expression was evaluated in clinical adenocarcinoma samples from 105 patients with GC by immunohistochemistry based on H-score. GH expression (H score ≥ 20; 33.3%) was significantly associated with a poor disease specific survival (DSS) and invasiveness in all samples with P=0.029 and P=0.013, respectively. In addition, it is also associated with shorter DSS and OS in poorly differentiated tumors with P=0.033 and P=0.045, respectively. Particularly, with patients ≥ 65 years of age, GH expression is also significantly associated with the stages (P=0.023), differentiation grade (P=0.038), and invasiveness (P=0.026) of the cancer. Sorted GC NCI-N87 cells with high level of endogenous GH showed higher proliferative activity compared with low-GH-expressing cells based on PCNA expression. Micro-western array analysis on high-GH-expressing GC cells indicated an upregulation in HER2-related signaling proteins including phospho-AKT/P38/JNK and Cyclin D1/Cyclin E1 proteins. Moreover, GH level was shown to be correlated with expression of total HER2 and caveolin-1 in GC cells. Immunoprecipitation study suggested that there are potential interactions among GH, caveolin-1, and HER2. In conclusions, GH level was significantly associated with the worse survival and disease progression in GC patients, especially in older patients. Enhanced cell proliferation activity through interactions among GH, HER2, and caveolin-1 interactions may contribute to GH induced tumor promotion signaling in GC. GH-targeting therapy may be a viable option for the treatment of GC patients.
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Affiliation(s)
- Hui-Ting Hsu
- Department of Pathology, Changhua Christian HospitalChanghua, Taiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan
- School of Medicine, Chung Shan Medical UniversityTaichung, Taiwan
- Department of Pathology, China Medical University HospitalTaichung, Taiwan
| | | | | | | | | | - Ming-Tai Hsing
- Department of Neurosurgery, Changhua Christian HospitalChanghua, Taiwan
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14
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Matsumoto Y, Ju T. Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors. Cancers (Basel) 2023; 15:3536. [PMID: 37509200 PMCID: PMC10377354 DOI: 10.3390/cancers15143536] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/01/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, and glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins and glycolipids, is diverse in their compositions and structures. Normal cells have their unique array of glycans or glycome which play pivotal roles in many biological processes. The glycan structures in cancer cells, however, are often altered, some having unique structures which are termed as tumor-associated carbohydrate antigens (TACAs). TACAs as tumor biomarkers are glycan epitopes themselves, or glycoconjugates. Some of those TACAs serve as tumor glyco-biomarkers in clinical practice, while others are the immune therapeutic targets for treatment of cancers. A monoclonal antibody (mAb) to GD2, an intermediate of sialic-acid containing glycosphingolipids, is an example of FDA-approved immune therapy for neuroblastoma indication in young adults and many others. Strategies for targeting the aberrant glycans are currently under development, and some have proceeded to clinical trials. In this review, we summarize the currently established and most promising aberrant glycosylation as therapeutic targets for solid tumors.
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Affiliation(s)
- Yasuyuki Matsumoto
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Tongzhong Ju
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
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15
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Freitas R, Peixoto A, Ferreira E, Miranda A, Santos LL, Ferreira JA. Immunomodulatory glycomedicine: Introducing next generation cancer glycovaccines. Biotechnol Adv 2023; 65:108144. [PMID: 37028466 DOI: 10.1016/j.biotechadv.2023.108144] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/17/2023] [Accepted: 03/30/2023] [Indexed: 04/09/2023]
Abstract
Cancer remains a leading cause of death worldwide due to the lack of safer and more effective therapies. Cancer vaccines developed from neoantigens are an emerging strategy to promote protective and therapeutic anti-cancer immune responses. Advances in glycomics and glycoproteomics have unveiled several cancer-specific glycosignatures, holding tremendous potential to foster effective cancer glycovaccines. However, the immunosuppressive nature of tumours poses a major obstacle to vaccine-based immunotherapy. Chemical modification of tumour associated glycans, conjugation with immunogenic carriers and administration in combination with potent immune adjuvants constitute emerging strategies to address this bottleneck. Moreover, novel vaccine vehicles have been optimized to enhance immune responses against otherwise poorly immunogenic cancer epitopes. Nanovehicles have shown increased affinity for antigen presenting cells (APCs) in lymph nodes and tumours, while reducing treatment toxicity. Designs exploiting glycans recognized by APCs have further enhanced the delivery of antigenic payloads, improving glycovaccine's capacity to elicit innate and acquired immune responses. These solutions show potential to reduce tumour burden, while generating immunological memory. Building on this rationale, we provide a comprehensive overview on emerging cancer glycovaccines, emphasizing the potential of nanotechnology in this context. A roadmap towards clinical implementation is also delivered foreseeing advances in glycan-based immunomodulatory cancer medicine.
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Affiliation(s)
- Rui Freitas
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
| | - Eduardo Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal
| | - Andreia Miranda
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal; Health School of University Fernando Pessoa, 4249-004 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal; Department of Surgical Oncology, Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal.
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16
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Hu Y, Li Y, Yao Z, Huang F, Cai H, Liu H, Zhang X, Zhang J. Immunotherapy: Review of the Existing Evidence and Challenges in Breast Cancer. Cancers (Basel) 2023; 15:563. [PMID: 36765522 PMCID: PMC9913569 DOI: 10.3390/cancers15030563] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Breast cancer (BC) is a representative malignant tumor that affects women across the world, and it is the main cause of cancer-related deaths in women. Although a large number of treatment methods have been developed for BC in recent years, the results are sometimes unsatisfying. In recent years, treatments of BC have been expanded with immunotherapy. In our article, we list some tumor markers related to immunotherapy for BC. Moreover, we introduce the existing relatively mature immunotherapy and the markers' pathogenesis are involved. The combination of immunotherapy and other therapies for BC are introduced in detail, including the combination of immunotherapy and chemotherapy, the combined use of immunosuppressants and chemotherapy drugs, immunotherapy and molecular targeted therapy. We summarize the clinical effects of these methods. In addition, this paper also makes a preliminary exploration of the combination of immunotherapy, radiotherapy, and nanotechnology for BC.
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Affiliation(s)
- Yun Hu
- Department of Breast Cancer, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Yan Li
- Department of Radiology, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Zhangcheng Yao
- Department of Radiology, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Fenglin Huang
- Department of Radiology, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Hongzhou Cai
- Department of Radiology, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Hanyuan Liu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Xiaoyi Zhang
- Department of Radiology, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Junying Zhang
- Department of Radiology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
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17
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Cancer Vaccines for Triple-Negative Breast Cancer: A Systematic Review. Vaccines (Basel) 2023; 11:vaccines11010146. [PMID: 36679991 PMCID: PMC9866612 DOI: 10.3390/vaccines11010146] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the poorest outcomes, and is associated with a high risk of relapse and metastasis. The treatment choices for this malignancy have been confined to conventional chemotherapeutic agents, due to a lack of expression of the canonical molecular targets. Immunotherapy has been recently changing the treatment paradigm for many types of tumors, and the approach of evoking active immune responses in the milieu of breast tumors through cancer vaccines has been introduced as one of the most novel immunotherapeutic approaches. Accordingly, a number of vaccines for the treatment or prevention of recurrence have been developed and are currently being studied in TNBC patients, while none have yet received any approvals. To elucidate the efficacy and safety of these vaccines, we performed a systematic review of the available literature on the topic. After searching the PubMed, Scopus, Web of Science, Embase, Cochrane CENTRAL, and Google Scholar databases, a total of 5701 results were obtained, from which 42 clinical studies were eventually included based on the predefined criteria. The overall quality of the included studies was acceptable. However, due to a lack of reporting outcomes of survival or progression in some studies (which were presented as conference abstracts) as well as the heterogeneity of the reported outcomes and study designs, we were not able to carry out a meta-analysis. A total of 32 different vaccines have so far been evaluated in TNBC patients, with the majority belonging to the peptide-based vaccine type. The other vaccines were in the cell or nucleic acid (RNA/DNA)-based categories. Most vaccines proved to be safe with low-grade, local adverse events and could efficiently evoke cellular immune responses; however, most trials were not able to demonstrate significant improvements in clinical indices of efficacy. This is in part due to the limited number of randomized studies, as well as the limited TNBC population of each trial. However, due to the encouraging results of the currently published trials, we anticipate that this strategy could show its potential through larger, phase III randomized studies in the near future.
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18
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Peric L, Vukadin S, Petrovic A, Kuna L, Puseljic N, Sikora R, Rozac K, Vcev A, Smolic M. Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer. Biomedicines 2022; 10:3265. [PMID: 36552021 PMCID: PMC9775348 DOI: 10.3390/biomedicines10123265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/25/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
Although we are lately witnessing major improvements in breast cancer treatment and patient outcomes, there is still a significant proportion of patients not receiving efficient therapy. More precisely, patients with triple-negative breast cancer or any type of metastatic disease. Currently available prognostic and therapeutic biomarkers are not always applicable and oftentimes lack precision. The science of glycans is a relatively new scientific approach to better characterize malignant transformation and tumor progression. In this review, we summarize the most important information about glycosylation characteristics in breast cancer cells and how different glycoproteins and enzymes involved in glycosylation could serve as more precise biomarkers, as well as new therapeutic targets.
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Affiliation(s)
- Luka Peric
- Department of Oncology, University Hospital Osijek, 31000 Osijek, Croatia
| | - Sonja Vukadin
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ana Petrovic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Nora Puseljic
- Pediatric Clinic, University Hospital Osijek, 31000 Osijek, Croatia
| | - Renata Sikora
- Department of Dental Medicine, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Karla Rozac
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Aleksandar Vcev
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
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19
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Sungsuwan S, Wu X, Shaw V, Kavunja H, McFall-Boegeman H, Rashidijahanabad Z, Tan Z, Lang S, Tahmasebi Nick S, Lin PH, Yin Z, Ramadan S, Jin X, Huang X. Structure Guided Design of Bacteriophage Qβ Mutants as Next Generation Carriers for Conjugate Vaccines. ACS Chem Biol 2022; 17:3047-3058. [PMID: 35142488 PMCID: PMC9363528 DOI: 10.1021/acschembio.1c00906] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Vaccines are critical tools to treat and prevent diseases. For an effective conjugate vaccine, the carrier is crucial, but few carriers are available for clinical applications. In addition, a drawback of current protein carriers is that high levels of antibodies against the carrier are induced by the conjugate vaccine, which are known to interfere with the immune responses against the target antigen. To overcome these challenges, we obtained the near atomic resolution crystal structure of an emerging protein carrier, i.e., the bacteriophage Qβ virus like particle. On the basis of the detailed structural information, novel mutants of bacteriophage Qβ (mQβ) have been designed, which upon conjugation with tumor associated carbohydrate antigens (TACAs), a class of important tumor antigens, elicited powerful anti-TACA IgG responses and yet produced lower levels of anticarrier antibodies as compared to those from the wild type Qβ-TACA conjugates. In a therapeutic model against an aggressive breast cancer in mice, 100% unimmunized mice succumbed to tumors in just 12 days even with chemotherapy. In contrast, 80% of mice immunized with the mQβ-TACA conjugate were completely free from tumors. Besides TACAs, to aid in the development of vaccines to protect against COVID-19, the mQβ based conjugate vaccine has been shown to induce high levels of IgG antibodies against peptide antigens from the SARS-CoV-2 virus, demonstrating its generality. Thus, mQβ is a promising next-generation carrier platform for conjugate vaccines, and structure-based rational design is a powerful strategy to develop new vaccine carriers.
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Affiliation(s)
- Suttipun Sungsuwan
- Virology and Cell Technology Research Team, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand
| | - Xuanjun Wu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao, Shandong 266237, China
| | | | - Herbert Kavunja
- Iaso Therapeutics Inc., 4942 Dawn Avenue, East Lansing, Michigan 48823, United States
| | | | | | | | | | | | | | | | - Sherif Ramadan
- Chemistry Department, Faculty of Science, Benha University, Benha, Qaliobiya 13518, Egypt
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Shivatare SS, Shivatare VS, Wong CH. Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments. Chem Rev 2022; 122:15603-15671. [PMID: 36174107 PMCID: PMC9674437 DOI: 10.1021/acs.chemrev.1c01032] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glycoconjugates are major constituents of mammalian cells that are formed via covalent conjugation of carbohydrates to other biomolecules like proteins and lipids and often expressed on the cell surfaces. Among the three major classes of glycoconjugates, proteoglycans and glycoproteins contain glycans linked to the protein backbone via amino acid residues such as Asn for N-linked glycans and Ser/Thr for O-linked glycans. In glycolipids, glycans are linked to a lipid component such as glycerol, polyisoprenyl pyrophosphate, fatty acid ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined and biosynthetically understood, especially those associated with human diseases, and are accessible to new drug, diagnostic, and therapeutic developments. This review describes the status and new advances in the biological study and therapeutic applications of natural and synthetic glycoconjugates, including proteoglycans, glycoproteins, and glycolipids. The scope, limitations, and novel methodologies in the synthesis and clinical development of glycoconjugates including vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., and their future prospectus are discussed.
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Affiliation(s)
- Sachin S Shivatare
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Vidya S Shivatare
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Chi-Huey Wong
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
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21
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Rugo HS, Cortes J, Barrios CH, Cabrera P, Xu B, Huang CS, Kim SB, Melisko M, Nanda R, Pieńkowski T, Rapoport BL, Schwab R. GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer. Future Oncol 2022; 18:3801-3813. [PMID: 36268941 DOI: 10.2217/fon-2022-0812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.
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Affiliation(s)
- Hope S Rugo
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Javier Cortes
- International Breast Cancer Center (IBCC), Barcelona, Spain
| | - Carlos H Barrios
- Centro de Pesquisa Clínica, Hospital São Lucas, Porto Alegre, Brazil
| | - Paula Cabrera
- Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Binghe Xu
- Cancer Hospital, Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | | | - Sung-Bae Kim
- Asan Medical Center, University of Ulsan, Seoul, Republic of Korea
| | - Michelle Melisko
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Rita Nanda
- University of Chicago Medicine, Chicago, IL, USA
| | - Tadeusz Pieńkowski
- Department of Oncology & Breast Diseases, Medical Center of Postgraduate Education, Warsaw, Poland
| | | | - Richard Schwab
- Moores Cancer Center at University of California San Diego Health, La Jolla, CA, USA
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22
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Ribeiro R, Carvalho MJ, Goncalves J, Moreira JN. Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities. Front Mol Biosci 2022; 9:903065. [PMID: 36060249 PMCID: PMC9437219 DOI: 10.3389/fmolb.2022.903065] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/13/2022] [Indexed: 12/24/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer that represents 15-20% of breast tumors and is more prevalent in young pre-menopausal women. It is the subtype of breast cancers with the highest metastatic potential and recurrence at the first 5 years after diagnosis. In addition, mortality increases when a complete pathological response is not achieved. As TNBC cells lack estrogen, progesterone, and HER2 receptors, patients do not respond well to hormone and anti-HER2 therapies, and conventional chemotherapy remains the standard treatment. Despite efforts to develop targeted therapies, this disease continues to have a high unmet medical need, and there is an urgent demand for customized diagnosis and therapeutics. As immunotherapy is changing the paradigm of anticancer treatment, it arises as an alternative treatment for TNBC patients. TNBC is classified as an immunogenic subtype of breast cancer due to its high levels of tumor mutational burden and presence of immune cell infiltrates. This review addresses the implications of these characteristics for the diagnosis, treatment, and prognosis of the disease. Herein, the role of immune gene signatures and tumor-infiltrating lymphocytes as biomarkers in TNBC is reviewed, identifying their application in patient diagnosis and stratification, as well as predictors of efficacy. The expression of PD-L1 expression is already considered to be predictive of response to checkpoint inhibitor therapy, but the challenges regarding its value as biomarker are described. Moreover, the rationales for different formats of immunotherapy against TNBC currently under clinical research are discussed, and major clinical trials are highlighted. Immune checkpoint inhibitors have demonstrated clinical benefit, particularly in early-stage tumors and when administered in combination with chemotherapy, with several regimens approved by the regulatory authorities. The success of antibody-drug conjugates and research on other emerging approaches, such as vaccines and cell therapies, will also be addressed. These advances give hope on the development of personalized, more effective, and safe treatments, which will improve the survival and quality of life of patients with TNBC.
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Affiliation(s)
- Rita Ribeiro
- CNC—Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal
- iMed.ULisboa—Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
| | - Maria João Carvalho
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
- CHUC—Coimbra Hospital and University Centre, Department of Gynaecology, Coimbra, Portugal
- Univ Coimbra—University Clinic of Gynaecology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- iCBR—Institute for Clinical and Biomedical Research Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, Coimbra, Portugal
| | - João Goncalves
- iMed.ULisboa—Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - João Nuno Moreira
- CNC—Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
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23
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Sorieul C, Papi F, Carboni F, Pecetta S, Phogat S, Adamo R. Recent advances and future perspectives on carbohydrate-based cancer vaccines and therapeutics. Pharmacol Ther 2022; 235:108158. [PMID: 35183590 DOI: 10.1016/j.pharmthera.2022.108158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022]
Abstract
Carbohydrates are abundantly expressed on the surface of both eukaryotic and prokaryotic cells, often as post translational modifications of proteins. Glycoproteins are recognized by the immune system and can trigger both innate and humoral responses. This feature has been harnessed to generate vaccines against polysaccharide-encapsulated bacteria such as Streptococcus pneumoniae, Hemophilus influenzae type b and Neisseria meningitidis. In cancer, glycosylation plays a pivotal role in malignancy development and progression. Since glycans are specifically expressed on the surface of tumor cells, they have been targeted for the discovery of anticancer preventive and therapeutic treatments, such as vaccines and monoclonal antibodies. Despite the various efforts made over the last years, resulting in a series of clinical studies, attempts of vaccination with carbohydrate-based candidates have proven unsuccessful, primarily due to the immune tolerance often associated with these glycans. New strategies are thus deployed to enhance carbohydrate-based cancer vaccines. Moreover, lessons learned from glycan immunobiology paved the way to the development of new monoclonal antibodies specifically designed to recognize cancer-bound carbohydrates and induce tumor cell killing. Herein we provide an overview of the immunological principles behind the immune response towards glycans and glycoconjugates and the approaches exploited at both preclinical and clinical level to target cancer-associated glycans for the development of vaccines and therapeutic monoclonal antibodies. We also discuss gaps and opportunities to successfully advance glycan-directed cancer therapies, which could provide patients with innovative and effective treatments.
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24
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Zhou J, Wang L, Peng C, Peng F. Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology. Front Pharmacol 2022; 13:886198. [PMID: 35784750 PMCID: PMC9242535 DOI: 10.3389/fphar.2022.886198] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.
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Affiliation(s)
- Jianbo Zhou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Li Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
| | - Fu Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
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25
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Generation of glycan-specific nanobodies. Cell Chem Biol 2022; 29:1353-1361.e6. [PMID: 35705094 DOI: 10.1016/j.chembiol.2022.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 02/21/2022] [Accepted: 05/23/2022] [Indexed: 11/21/2022]
Abstract
The development of antibodies that target specific glycan structures on cancer cells or human pathogens poses a significant challenge due to the immense complexity of naturally occurring glycans. Automated glycan assembly enables the production of structurally homogeneous glycans in amounts that are difficult to derive from natural sources. Nanobodies (Nbs) are the smallest antigen-binding domains of heavy-chain-only antibodies (hcAbs) found in camelids. To date, the development of glycan-specific Nbs using synthetic glycans has not been reported. Here, we use defined synthetic glycans for alpaca immunization to elicit glycan-specific hcAbs, and describe the identification, isolation, and production of a Nb specific for the tumor-associated carbohydrate antigen Globo-H. The Nb binds the terminal fucose of Globo-H and recognizes synthetic Globo-H in solution and native Globo-H on breast cancer cells with high specificity. These results demonstrate the potential of our approach for generating glycan-targeting Nbs to be used in biomedical and biotechnological applications.
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26
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Hung JT, Chen IJ, Ueng SH, Huang CS, Chen SC, Chen MY, Lin YC, Lin CY, Campbell MJ, Rugo HS, Yu AL. The clinical relevance of humoral immune responses to Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 and expression of Globo H in metastatic breast cancer. J Immunother Cancer 2022; 10:jitc-2021-004312. [PMID: 35732348 PMCID: PMC9226869 DOI: 10.1136/jitc-2021-004312] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 11/30/2022] Open
Abstract
An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p<0.0001) and IgG titers (p<0.0001) than those with <1:320. Moreover, the median PFS appears to be longer for patients with anti-GH IgM ≥1:320 within first 4 weeks than those with anti-GH IgM titer <1:320 (11.1 vs 7.3 months, p=0.164), but not statistically significant. Among patients with H score ≥80 for GH expression by immunohistochemistry, the vaccination group (n=42) seemed to have better PFS than the placebo group (n=23) (HR=0.59; 95% CI: 0.32 to 1.10, p=0.10), but the difference did not reach statistical significance. In addition, peak levels of anti-GH IgM were higher in patients who had lower percentage of activated regulatory T cells (Treg cells; CD4+CD45RA-Foxp3high) at baseline than those who had higher activated Treg cells (p=0.042). This study demonstrates that adagloxad simolenin induced both IgG and IgM antibodies against GH. Anti-GH IgM ≥1:320 within first 4 weeks or low activated Treg cells at baseline may help to select patients who are likely to produce a higher level of GH-specific IgM and IgG in the future.
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Affiliation(s)
- Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | | | - Shir-Hwa Ueng
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chiun-Sheng Huang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shin-Cheh Chen
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | | | - Yung-Chang Lin
- Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Michael J Campbell
- Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, California, USA
| | - Hope S Rugo
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan .,Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.,Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
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27
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Xie X, Lee J, Fuson JA, Liu H, Iwase T, Yun K, Margain C, Tripathy D, Ueno NT. Emerging drug targets for triple-negative breast cancer: a guided tour of the preclinical landscape. Expert Opin Ther Targets 2022; 26:405-425. [PMID: 35574694 PMCID: PMC11972560 DOI: 10.1080/14728222.2022.2077188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/10/2022] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is the most fatal molecular subtype of breast cancer because of its aggressiveness and resistance to chemotherapy. FDA-approved therapies for TNBC are limited to poly(ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and trophoblast cell surface antigen 2-targeted antibody-drug conjugate. Therefore, developing a novel effective targeted therapy for TNBC is an urgent unmet need. AREAS COVERED In this narrative review, we discuss emerging targets for TNBC treatment discovered in early translational studies. We focus on cancer cell membrane molecules, hyperactive intracellular signaling pathways, and the tumor microenvironment (TME) based on their druggability, therapeutic potency, specificity to TNBC, and application in immunotherapy. EXPERT OPINION The significant challenges in the identification and validation of TNBC-associated targets are 1) application of appropriate genetic, molecular, and immunological approaches for modulating the target, 2) establishment of a proper mouse model that accurately represents the human immune TME, 3) TNBC molecular heterogeneity, and 4) failure translation of preclinical findings to clinical practice. To overcome those difficulties, future research needs to apply novel technology, such as single-cell RNA sequencing, thermostable group II intron reverse transcriptase sequencing, and humanized mouse models. Further, combination treatment targeting multiple pathways in both the TNBC tumor and its TME is essential for effective disease control.
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Affiliation(s)
- Xuemei Xie
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jangsoon Lee
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jon A. Fuson
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huey Liu
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Toshiaki Iwase
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kyuson Yun
- Research Institute at Houston Methodist, Weill Cornell Medical College, Houston, TX 77030, USA
| | | | - Debu Tripathy
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoto T. Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Cancer Biology and Therapeutics, University of Hawai’i Cancer Center, Honolulu, HI 96813, USA
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28
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Pherez-Farah A, López-Sánchez RDC, Villela-Martínez LM, Ortiz-López R, Beltrán BE, Hernández-Hernández JA. Sphingolipids and Lymphomas: A Double-Edged Sword. Cancers (Basel) 2022; 14:2051. [PMID: 35565181 PMCID: PMC9104519 DOI: 10.3390/cancers14092051] [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: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 11/24/2022] Open
Abstract
Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways. Many comprehensive reviews describing their role in cancer exist, but because most research has been conducted in solid malignancies, evidence in lymphomagenesis is somewhat limited. In this review, we summarize key aspects of sphingolipid biochemistry and discuss their known impact in cancer biology, with a particular focus on lymphomas and possible therapeutical strategies against them.
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Affiliation(s)
- Alfredo Pherez-Farah
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico
| | | | - Luis Mario Villela-Martínez
- Facultad de Medicina, Universidad Autónoma de Sinaloa, Culiacán Rosales 80030, Sinaloa, Mexico
- Hospital Fernando Ocaranza, ISSSTE, Hermosillo 83190, Sonora, Mexico
- Centro Médico Dr. Ignacio Chávez, ISSSTESON, Hermosillo 83000, Sonora, Mexico
| | - Rocío Ortiz-López
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico
| | - Brady E Beltrán
- Hospital Edgardo Rebagliati Martins, Lima 15072, Peru
- Instituto de Investigaciones en Ciencias Biomédicas, Universidad Ricardo Palma, Lima 1801, Peru
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29
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Berois N, Pittini A, Osinaga E. Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives. Cancers (Basel) 2022; 14:cancers14030645. [PMID: 35158915 PMCID: PMC8833780 DOI: 10.3390/cancers14030645] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Aberrant glycosylation is a common feature of many cancers, and it plays crucial roles in tumor development and biology. Cancer progression can be regulated by several physiopathological processes controlled by glycosylation, such as cell–cell adhesion, cell–matrix interaction, epithelial-to-mesenchymal transition, tumor proliferation, invasion, and metastasis. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs), which are suitable for selective cancer targeting, as well as novel antitumor immunotherapy approaches. This review summarizes the strategies developed in cancer immunotherapy targeting TACAs, analyzing molecular and cellular mechanisms and state-of-the-art methods in clinical oncology. Abstract Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.
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Affiliation(s)
- Nora Berois
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Correspondence: (N.B.); (E.O.)
| | - Alvaro Pittini
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Eduardo Osinaga
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Correspondence: (N.B.); (E.O.)
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30
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Chen CY, Lin YW, Wang SW, Lin YC, Cheng YY, Ren CT, Wong CH, Wu CY. Synthesis of Azido-Globo H Analogs for Immunogenicity Evaluation. ACS CENTRAL SCIENCE 2022; 8:77-85. [PMID: 35106375 PMCID: PMC8796297 DOI: 10.1021/acscentsci.1c01277] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Indexed: 06/14/2023]
Abstract
Globo H (GH) is a tumor-associated carbohydrate antigen (TACA), and GH conjugations have been evaluated as potential cancer vaccines. However, like all carbohydrate-based vaccines, low immunogenicity is a major issue. Modifications of the TACA increase its immunogenicity, but the systemic modification on GH is challenging and the synthesis is cumbersome. In this study, we synthesized several azido-GH analogs for evaluation, using galactose oxidase to selectively oxidize C6-OH of the terminal galactose or N-acetylgalactosamine on lactose, Gb3, Gb4, and SSEA3 into C6 aldehyde, which was then transformed chemically to the azido group. The azido-derivatives were further glycosylated to azido-GH analogs by glycosyltransferases coupled with sugar nucleotide regeneration. These azido-GH analogs and native GH were conjugated to diphtheria toxoid cross-reactive material CRM197 for vaccination with C34 adjuvant in mice. Glycan array analysis of antisera indicated that the azido-GH glycoconjugate with azide at Gal-C6 of Lac (1-CRM197) elicited the highest antibody response not only to GH, SSEA3, and SSEA4, which share the common SSEA3 epitope, but also to MCF-7 cancer cells, which express these Globo-series glycans.
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Affiliation(s)
- Chiang-Yun Chen
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Chemical
Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
- Department
of Chemistry, National Taiwan University, Taipei, 106, Taiwan
| | - Yu-Wei Lin
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Szu-Wen Wang
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Institute
of Biochemical Sciences, National Taiwan
University, Taipei 106, Taiwan
| | - Yung-Chu Lin
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Yang-Yu Cheng
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Institute
of Biochemistry and Molecular Biology, National
Yang-Ming University, Taipei 112, Taiwan
| | - Chien-Tai Ren
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Chi-Huey Wong
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Chemical
Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
- Institute
of Biochemical Sciences, National Taiwan
University, Taipei 106, Taiwan
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
| | - Chung-Yi Wu
- Genomics
Research Center, Academia Sinica, Taipei 115, Taiwan
- Chemical
Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
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31
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He R, Zang J, Zhao Y, Dong H, Li Y. Nanotechnology-Based Approaches to Promote Lymph Node Targeted Delivery of Cancer Vaccines. ACS Biomater Sci Eng 2022; 8:406-423. [PMID: 35005881 DOI: 10.1021/acsbiomaterials.1c01274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Vaccines are a promising immunotherapy that awakens the human immune system to inhibit and eliminate cancer with fewer side effects compared with traditional radiotherapy and chemotherapy. Although cancer vaccines have shown some efficacy, there are still troublesome bottlenecks to expand their benefits in the clinic, including weak immune effects and limited therapeutic outcomes. In the past few years, in addition to neoantigen screening, a main branch of the efforts has been devoted to promoting the lymph nodes (LNs) targeting of cancer vaccines and the cross-presentation of antigens by dendritic cells (DCs), two cardinal stages in effective initiation of the immune response. Especially, nanomaterials have shown hopeful biomedical applications in the improvement of vaccine effectiveness. This Review briefly outlines the possible mechanisms by which nanoparticle properties affect LN targeting and antigen cross-presentation and then gives an overview of state-of-the-art advances in improving these biological outcomes with nanotechnology.
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Affiliation(s)
- Ruiqing He
- Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jie Zang
- Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yuge Zhao
- Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
| | - Haiqing Dong
- Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yongyong Li
- Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
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32
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Hung TH, Hung JT, Wu CE, Huang Y, Lee CW, Yeh CT, Chung YH, Lo FY, Lai LC, Tung JK, Yu J, Yeh CN, Yu AL. Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma. Hepatol Commun 2022; 6:194-208. [PMID: 34558839 PMCID: PMC8710794 DOI: 10.1002/hep4.1800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/09/2021] [Accepted: 07/14/2021] [Indexed: 12/29/2022] Open
Abstract
Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H-specific antibody in thioacetamide (TAA)-induced ICC in rats. Globo H-ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti-Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.
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Affiliation(s)
- Tsai-Hsien Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chiao-En Wu
- Department of Hematology-Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Yenlin Huang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Chien-Wei Lee
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hsiu Chung
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Fei-Yun Lo
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Li-Chun Lai
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - John K Tung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Pediatrics, University of California in San Diego, San Diego, CA
- Chang Gung University, Taoyuan, Taiwan
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Corti C, Giachetti PPMB, Eggermont AMM, Delaloge S, Curigliano G. Therapeutic vaccines for breast cancer: Has the time finally come? Eur J Cancer 2022; 160:150-174. [PMID: 34823982 PMCID: PMC8608270 DOI: 10.1016/j.ejca.2021.10.027] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022]
Abstract
The ability to exploit the immune system as a weapon against cancer has revolutionised the treatment of cancer patients, especially through immune checkpoint inhibitors (ICIs). However, ICIs demonstrated a modest benefit in treating breast cancer (BC), with the exception of certain subsets of triple-negative BCs. An immune-suppressive tumour microenvironment (TME), typically present in BC, is an important factor in the poor response to immunotherapy. After almost two decades of poor clinical trial results, cancer vaccines (CVs), an active immunotherapy, have come back in the spotlight because of some technological advancements, ultimately boosted by coronavirus disease 2019 pandemic. In particular, neoantigens are emerging as the preferred targets for CVs, with gene-based and viral vector-based platforms in development. Moreover, lipid nanoparticles proved to be immunogenic and efficient delivery vehicles. Past clinical trials investigating CVs focused especially on the metastatic disease, where the TME is more likely compromised by inhibitory mechanisms. In this sense, favouring the use of CVs as monotherapy in premalignant or in the adjuvant setting and establishing combination treatments (i.e. CV plus ICI) in late-stage disease are promising strategies. This review provides a full overview of the past and current breast cancer vaccine landscape.
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Affiliation(s)
- Chiara Corti
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
| | - Pier P M B Giachetti
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
| | - Alexander M M Eggermont
- Princess Máxima Center, Utrecht, the Netherlands; Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France
| | - Suzette Delaloge
- Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy.
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Disis ML, Cecil DL. Breast cancer vaccines for treatment and prevention. Breast Cancer Res Treat 2021; 191:481-489. [PMID: 34846625 DOI: 10.1007/s10549-021-06459-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/15/2021] [Indexed: 12/22/2022]
Abstract
Breast cancer is immunogenic and a variety of vaccines have been designed to boost immunity directed against the disease. The components of a breast cancer vaccine, the antigen, the delivery system, and the adjuvant, can have a significant impact on vaccine immunogenicity. There have been numerous immunogenic proteins identified in all subtypes of breast cancer. The majority of these antigens are weakly immunogenic nonmutated tumor-associated proteins. Mutated proteins and neoantigen epitopes are found only in a small minority of patients and are enriched in the triple negative subtype. Several vaccines have advanced to large randomized Phase II or Phase III clinical trials. None of these trials met their primary endpoint of either progression-free or overall survival. Despite these set-backs investigators have learned important lessons regarding the clinical application of breast cancer vaccines from the type of immune response needed for tumor eradication, Type I T-cell immunity, to the patient populations most likely to benefit from vaccination. Many therapeutic breast cancer vaccines are now being tested in combination with other forms of immune therapy or chemotherapy and radiation. Breast cancer vaccines as single agents are now studied in the context of the prevention of relapse or development of disease. Newer approaches are designing vaccines to prevent breast cancer by intercepting high-risk lesions such as ductal carcinoma in situ to limit the progression of these tumors to invasive cancer. There are also several efforts to develop vaccines for the primary prevention of breast cancer by targeting antigens expressed during breast cancer initiation.
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Affiliation(s)
- Mary L Disis
- Cancer Vaccine Institute, University of Washington, Seattle, WA, USA.
| | - Denise L Cecil
- Cancer Vaccine Institute, University of Washington, Seattle, WA, USA
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Sigal DS, Hermel DJ, Hsu P, Pearce T. The role of Globo H and SSEA-4 in the development and progression of cancer, and their potential as therapeutic targets. Future Oncol 2021; 18:117-134. [PMID: 34734786 DOI: 10.2217/fon-2021-1110] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Glycans, chains of sugar molecules found conjugated to cell proteins and lipids, contribute to their growth, movement and differentiation. Aberrant glycosylation is a hallmark of several medical conditions including tumorigenesis. Glycosphingolipids (GSLs), consisting of glycans conjugated to a lipid (ceramide) core, are found in the lipid bilayer of eukaryotic cell membranes. GSLs, play an active role in cell processes. Several GSLs are expressed by human embryonic stem cells and have been found to be overexpressed in several types of cancer. In this review, we discuss the data, hypotheses and perspectives related to the GSLs Globo H and SSEA-4.
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Affiliation(s)
- Darren S Sigal
- Director, GI Oncology, Scripps Clinic & Scripps MD Anderson Cancer Center, 10710 N Torrey Pines Road, La Jolla, CA 92037, USA
| | - David J Hermel
- Scripps Clinic & Scripps MD Anderson Cancer Center, 10710 N Torrey Pines Road, LA Jolla, CA 92037, USA
| | - Pei Hsu
- Medical Advisor, Medical Affairs & Clinical Development, OBI Pharma Inc. 7F, No. 369, Zhongxiao E Road, Nangang District, Taipei City, 115, Taiwan
| | - Tillman Pearce
- Chief Medical Officer, OBI Pharma USA Inc., 6020 Cornerstone Court W, Suite 200, San Diego, CA 92121, USA
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36
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Zhai C, Zheng XJ, Song C, Ye XS. Synthesis and immunological evaluation of N-acyl modified Globo H derivatives as anticancer vaccine candidates. RSC Med Chem 2021; 12:1239-1243. [PMID: 34355188 PMCID: PMC8292959 DOI: 10.1039/d1md00067e] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Globo H is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target for antitumor vaccine or cancer immunotherapies. However, most TACAs are T-cell-independent, and they cannot induce powerful immune response due to their poor immunogenicity. To address this problem, herein, several Globo H analogues with modification on the N-acyl group were prepared through a preactivation-based glycosylation strategy from the non-reducing end to the reducing end. These modified Globo H derivatives were then conjugated with carrier protein CRM197 to form glycoconjugates as anticancer vaccine candidates, which were used in combination with adjuvant glycolipid C34 for immunological studies. The immunological effects of these synthetic vaccine candidates were evaluated on Balb/c mice. The results showed that the fluorine-modified N-acyl Globo H conjugates can induce higher titers of IgG antibodies that can recognize the naturally occurring Globo H antigen on the surface of cancer cells and can eliminate cancer cells in the presence of a complement, indicating the potential of these synthetic glycoconjugates as anticancer vaccine candidates.
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Affiliation(s)
- Canjia Zhai
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Xue Yuan Rd No. 38 Beijing 100191 China
| | - Xiu-Jing Zheng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Xue Yuan Rd No. 38 Beijing 100191 China
| | - Chengcheng Song
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Xue Yuan Rd No. 38 Beijing 100191 China
| | - Xin-Shan Ye
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Xue Yuan Rd No. 38 Beijing 100191 China
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37
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Hall PE, Schmid P. Emerging drugs for the treatment of triple-negative breast cancer: a focus on phase II immunotherapy trials. Expert Opin Emerg Drugs 2021; 26:131-147. [PMID: 33870839 DOI: 10.1080/14728214.2021.1916468] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Triple-negative breast cancer accounts for 10-20% of invasive breast cancers and is characterized by an aggressive phenotype and poor outcomes in the early and advanced settings compared to other breast cancer subtypes. Chemotherapy continues to be the mainstay of treatment, but recent advances have demonstrated the benefit of adding immune checkpoint inhibitors (ICIs) to chemotherapy regimens for patients with both early and advanced TNBC, particularly if PD-L1-positive. Despite these results, further improvements are needed.Areas covered: This review covers immunotherapy drugs which have recently completed, involved in ongoing or due to start phase II trials. This includes approaches to augment the response to existing ICIs, next-generation ICIs, combination treatments with targeted agents and drugs that target the tumor microenvironment. Potential development issues are also discussed.Expert opinion: The field of immunotherapy is developing rapidly and holds great promise for patients with TNBC. Promising avenues of research currently in phase II trials include targeting multiple immune checkpoints simultaneously and the addition of phosphatidylinositol 3-kinase (PI3K)/AKT inhibitors to ICI/chemotherapy regimens. A better understanding of the immunosuppressive role played by the tumor microenvironment has also been important. However, challenges remain, particularly regarding the need for more effective predictive biomarkers.
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Affiliation(s)
- Peter E Hall
- Dept. Of Medical Oncology, Barts Health NHS Trust, London, UK
| | - Peter Schmid
- Dept. Of Medical Oncology, Barts Health NHS Trust, London, UK.,Barts Cancer Institute, Queen Mary University of London, London, UK
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38
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Wang SH, Wu TJ, Lee CW, Yu J. Dissecting the conformation of glycans and their interactions with proteins. J Biomed Sci 2020; 27:93. [PMID: 32900381 PMCID: PMC7487937 DOI: 10.1186/s12929-020-00684-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/26/2020] [Indexed: 12/20/2022] Open
Abstract
The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem derives, in part, from the lack of technologies to quantitatively and qualitatively assess the complex assembling between a glycan and the targeted protein molecule. Since there is an unmet need for developing new sugar-targeted therapeutics, many investigators are searching for technology platforms to elucidate various types of molecular interactions within glycan-protein complexes and aid in the development of glycan-targeted therapies. Here we discuss three important technology platforms commonly used in the assessment of the complex assembly of glycosylated biomolecules, such as glycoproteins or glycosphingolipids: Biacore analysis, molecular docking, and molecular dynamics simulations. We will also discuss the structural investigation of glycosylated biomolecules, including conformational changes of glycans and their impact on molecular interactions within the glycan-protein complex. For glycoproteins, secreted protein acidic and rich in cysteine (SPARC), which is associated with various lung disorders, such as chronic obstructive pulmonary disease (COPD) and lung cancer, will be taken as an example showing that the core fucosylation of N-glycan in SPARC regulates protein-binding affinity with extracellular matrix collagen. For glycosphingolipids (GSLs), Globo H ceramide, an important tumor-associated GSL which is being actively investigated as a target for new cancer immunotherapies, will be used to demonstrate how glycan structure plays a significant role in enhancing angiogenesis in tumor microenvironments.
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Affiliation(s)
- Sheng-Hung Wang
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan, 333, Taiwan
| | - Tsai-Jung Wu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan, 333, Taiwan
| | - Chien-Wei Lee
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan, 333, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan, 333, Taiwan. .,Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
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39
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Yu J, Hung JT, Wang SH, Cheng JY, Yu AL. Targeting glycosphingolipids for cancer immunotherapy. FEBS Lett 2020; 594:3602-3618. [PMID: 32860713 DOI: 10.1002/1873-3468.13917] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/20/2020] [Accepted: 08/20/2020] [Indexed: 11/07/2022]
Abstract
Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.
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Affiliation(s)
- John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.,Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Sheng-Hung Wang
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Yan Cheng
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.,Department of Pediatrics, University of California in San Diego, La Jolla, CA, USA
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