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Liu D, Liu L, Li X, Wang S, Wu G, Che X. Advancements and Challenges in Peptide-Based Cancer Vaccination: A Multidisciplinary Perspective. Vaccines (Basel) 2024; 12:950. [PMID: 39204073 PMCID: PMC11359700 DOI: 10.3390/vaccines12080950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 09/03/2024] Open
Abstract
With the continuous advancements in tumor immunotherapy, researchers are actively exploring new treatment methods. Peptide therapeutic cancer vaccines have garnered significant attention for their potential in improving patient outcomes. Despite its potential, only a single peptide-based cancer vaccine has been approved by the U.S. Food and Drug Administration (FDA). A comprehensive understanding of the underlying mechanisms and current development status is crucial for advancing these vaccines. This review provides an in-depth analysis of the production principles and therapeutic mechanisms of peptide-based cancer vaccines, highlights the commonly used peptide-based cancer vaccines, and examines the synergistic effects of combining these vaccines with immunotherapy, targeted therapy, radiotherapy, and chemotherapy. While some studies have yielded suboptimal results, the potential of combination therapies remains substantial. Additionally, we addressed the management and adverse events associated with peptide-based cancer vaccines, noting their relatively higher safety profile compared to traditional radiotherapy and chemotherapy. Lastly, we also discussed the roles of adjuvants and targeted delivery systems in enhancing vaccine efficacy. In conclusion, this review comprehensively outlines the current landscape of peptide-based cancer vaccination and underscores its potential as a pivotal immunotherapy approach.
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Affiliation(s)
- Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Lei Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Xinghan Li
- Department of Stomatology, General Hospital of Northern Theater Command, Shenyang 110016, China;
| | - Shijin Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
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2
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Chen X, Sandrine IK, Yang M, Tu J, Yuan X. MUC1 and MUC16: critical for immune modulation in cancer therapeutics. Front Immunol 2024; 15:1356913. [PMID: 38361923 PMCID: PMC10867145 DOI: 10.3389/fimmu.2024.1356913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/18/2024] [Indexed: 02/17/2024] Open
Abstract
The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.
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Affiliation(s)
| | | | | | - Jingyao Tu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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3
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Kumar AR, Devan AR, Nair B, Nair RR, Nath LR. Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2022; 22:725-740. [PMID: 35301949 DOI: 10.2174/1568009622666220317090552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/14/2021] [Accepted: 12/21/2021] [Indexed: 02/08/2023]
Abstract
Mucin 1 (MUC 1) is a highly glycosylated tumor-associated antigen (TAA) overexpressed in hepatocellular carcinoma (HCC). This protein plays a critical role in various immune-mediated signaling pathways at its transcriptional and post-transcriptional levels, leading to immune evasion and metastasis in HCC. HCC cells maintain an immune-suppressive environment with the help of immunesuppressive tumor-associated antigens, resulting in a metastatic spread of the disease. The development of intense immunotherapeutic strategies to target tumor-associated antigen is critical to overcoming the progression of HCC. MUC 1 remains the most recognized tumor-associated antigen since its discovery over 30 years ago. A few promising immunotherapies targeting MUC 1 are currently under clinical trials, including CAR-T and CAR-pNK-mediated therapies. This review highlights the biosynthesis, significance, and clinical implication of MUC 1 as an immune target in HCC.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | | | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
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Liu Y, Tang L, Gao N, Diao Y, Zhong J, Deng Y, Wang Z, Jin G, Wang X. Synthetic MUC1 breast cancer vaccine containing a Toll-like receptor 7 agonist exerts antitumor effects. Oncol Lett 2020; 20:2369-2377. [PMID: 32782554 PMCID: PMC7400475 DOI: 10.3892/ol.2020.11762] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022] Open
Abstract
Adjuvant immunotherapy has recently emerged as a potential treatment strategy for breast cancer. The tumor-associated protein mucin 1 (MUC1) has received increasing attention due to its high expression in numerous types of common tumors, in which MUC1 acts as a cancer antigen. However, the simple mixed composition of an adjuvant and a peptide is not a sufficient rationale for a MUC1 peptide-based vaccine. The present study developed a novel Toll-like receptor 7 (TLR7) agonist-conjugated MUC1 peptide vaccine (T7-MUC1), which elicited an effective immune response and a robust antitumor effect in a mouse breast cancer model. In vitro, T7-MUC1 significantly increased the release of cytokines in mouse bone marrow dendritic cells and spleen lymphocytes, and induced the dendritic cell-cytokine-induced killer response against tumor cells with high MUC1 expression. In vivo, it was observed that the 4T1 tumor weights in mice immunized with the T7-MUC1 conjugate were reduced by ≥70% compared with those in the control group. Furthermore, the therapeutic responses in vivo were attributed to the increase in specific humoral and cellular immunity, including high antibody titers, antibody-dependent cell-mediated cytotoxicity and cytotoxic T-lymphocyte activity. The percentages of CD3+/CD8+ T-cells were significantly higher in the T7-MUC1 treatment group compared with those in the control group. Therefore, the results of the present study suggested that the T7-MUC1 vaccine inhibited tumor growth in mice and thus may have potential as a therapeutic candidate in clinical trials for breast cancer immunotherapy.
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Affiliation(s)
- Yu Liu
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China.,Department of Research and Education, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518001, P.R. China
| | - Li Tang
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China.,College of Physics and Optoelectronic Engineering, Key Laboratory of Optoelectronic Devices and Systems of The Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, Guangdong 518060, P.R. China
| | - Ningning Gao
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Yuwen Diao
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Jingjing Zhong
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Yongqiang Deng
- Department of Oral and Maxillofacial Surgery, Shenzhen University General Hospital, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Zhulin Wang
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Guangyi Jin
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
| | - Xiaodong Wang
- International Cancer Center, National-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518055, P.R. China
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5
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Yu H, Ye C, Li J, Pan C, Lin W, Chen H, Zhou Z, Ye Y. An altered HLA-A0201-restricted MUC1 epitope that could induce more efficient anti-tumor effects against gastric cancer. Exp Cell Res 2020; 390:111953. [PMID: 32156601 DOI: 10.1016/j.yexcr.2020.111953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/30/2022]
Abstract
MUC1 is a tumor-associated antigen (TAA) overexpressed in many tumor types, which makes it an attractive target for cancer immunotherapy. However, this marker is a non-mutated antigen without high immunogenicity. In this study, we designed several new altered peptides by replacing amino acids in their sequences, which were derived from a low-affinity MUC1 peptide, thus bypassing immune tolerance. Compared to the wild-type (WT) peptide, the altered MUC1 peptides (MUC11081-1089L2, MUC11156-1164L2, MUC11068-1076Y1) showed higher affinity to the HLA-A0201 molecule and stronger immunogenicity. Furthermore, these altered peptides resulted in the generation of more cytotoxic T lymphocytes (CTLs) that could cross-recognize gastric cancer cells expressing WT MUC1 peptides, in an HLA-A0201-restricted manner. In addition, M1.1 (MUC1950-958), a promising antitumor peptide that has been tested in multiple tumors, was not able to induce stronger antitumor responses. Collectively, our results demonstrated that altered peptides from MUC1, as potential HLA-A0201-restricted CTL epitopes, could serve as peptide vaccines or constitute components of peptide-loaded dendritic cell vaccines for gastric cancer treatment.
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Affiliation(s)
- Huahui Yu
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Chunmei Ye
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Jieyu Li
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Chunli Pan
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Wansong Lin
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Huijing Chen
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Zhifeng Zhou
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Yunbin Ye
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China; Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China.
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6
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Bhatia R, Gautam SK, Cannon A, Thompson C, Hall BR, Aithal A, Banerjee K, Jain M, Solheim JC, Kumar S, Batra SK. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev 2020; 38:223-236. [PMID: 30618016 DOI: 10.1007/s10555-018-09775-0] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.
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Affiliation(s)
- Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Christopher Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Bradley R Hall
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kasturi Banerjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Joyce C Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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7
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Ladoire S, Derangère V, Arnould L, Thibaudin M, Coudert B, Lorgis V, Desmoulins I, Chaix M, Fumoleau P, Ghiringhelli F. [The anti-tumor immune response in breast cancer: Update and therapeutic perspectives]. Ann Pathol 2017; 37:133-141. [PMID: 28159406 DOI: 10.1016/j.annpat.2016.12.012] [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: 12/07/2016] [Accepted: 12/08/2016] [Indexed: 11/18/2022]
Abstract
The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer.
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Affiliation(s)
- Sylvain Ladoire
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France; UFR des sciences de santé, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France.
| | - Valentin Derangère
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France; Département de pathologie et de biologie des tumeurs, centre Georges-François-Leclerc, 21000 Dijon, France
| | - Laurent Arnould
- Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France; Département de pathologie et de biologie des tumeurs, centre Georges-François-Leclerc, 21000 Dijon, France
| | - Marion Thibaudin
- UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France
| | - Bruno Coudert
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France
| | - Veronique Lorgis
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France
| | - Isabelle Desmoulins
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France
| | - Marie Chaix
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France; UFR des sciences de santé, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France
| | - Pierre Fumoleau
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; UFR des sciences de santé, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France
| | - François Ghiringhelli
- Département d'oncologie médicale, centre Georges-François-Leclerc, 21000 Dijon, France; Plateforme de transfert en biologie cancérologique, centre Georges-François-Leclerc, 21000 Dijon, France; UMR Inserm U866, faculté de médecine de Dijon, 21000 Dijon, France; UFR des sciences de santé, 21000 Dijon, France; Université de Bourgogne, 21000 Dijon, France
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Antonilli M, Rahimi H, Visconti V, Napoletano C, Ruscito I, Zizzari IG, Caponnetto S, Barchiesi G, Iadarola R, Pierelli L, Rughetti A, Bellati F, Panici PB, Nuti M. Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial. Int J Oncol 2016; 48:1369-78. [PMID: 26892612 PMCID: PMC4777599 DOI: 10.3892/ijo.2016.3386] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 01/13/2016] [Indexed: 12/21/2022] Open
Abstract
Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments.
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Affiliation(s)
- Morena Antonilli
- Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Hassan Rahimi
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Valeria Visconti
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Chiara Napoletano
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Ilary Ruscito
- Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Ilaria Grazia Zizzari
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Salvatore Caponnetto
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Giacomo Barchiesi
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Roberta Iadarola
- Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Luca Pierelli
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Aurelia Rughetti
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Filippo Bellati
- Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Pierluigi Benedetti Panici
- Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
| | - Marianna Nuti
- Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy
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Rivalland G, Loveland B, Mitchell P. Update on Mucin-1 immunotherapy in cancer: a clinical perspective. Expert Opin Biol Ther 2015; 15:1773-87. [PMID: 26453294 DOI: 10.1517/14712598.2015.1088519] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Mucin 1 (MUC1) is particularly well suited as a cancer immunotherapy target due to the elevated protein expression and aberrant forms associated with malignancy. A variety of therapeutic strategies have been explored, including antibodies intended to induce cancer cell destruction, and vaccinations with peptides, tumor extracts, and gene expression systems. AREAS COVERED MUC1 immunotherapeutic strategies have included vaccination with peptide sequences, glycan molecules, viruses, and dendritic cells, monoclonal antibodies and monoclonal antibody conjugates. Here we review the relevant clinical trials in each field of immunotherapy with particular focus on large and recently published trials. EXPERT OPINION Long clinical experience in the trial setting has reduced concerns of immunotherapy associated toxicities and inappropriate immune responses, with the main limitation (common to many experimental approaches) being a lack of clinical efficacy. However, there have been sufficient treatment-associated responses to justify continued pursuit of MUC1 targeted immunotherapies. The focus now should be on application to the relevant cancers under appropriate circumstances and combination with the emerging non-specific immunotherapy approaches such as the PD-1 pathway inhibitors.
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Affiliation(s)
- Gareth Rivalland
- a 1 Austin Health, Olivia Newton-John Cancer and Wellness Centre , Studley Rd, Heidelberg VIC 3084, Australia
| | - Bruce Loveland
- b 2 Burnet Institute, Centre for Biomedical Research , Melbourne VIC 3004, Australia
| | - Paul Mitchell
- c 3 Austin Health, Level 4, Olivia Newton-John Cancer and Wellness Centre , Studley Rd, Heidelberg VIC 3084, Australia +613 94 96 57 63 ; +613 94 57 66 98 ;
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Oberg AL, McKinney BA, Schaid DJ, Pankratz VS, Kennedy RB, Poland GA. Lessons learned in the analysis of high-dimensional data in vaccinomics. Vaccine 2015; 33:5262-70. [PMID: 25957070 DOI: 10.1016/j.vaccine.2015.04.088] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 04/16/2015] [Accepted: 04/23/2015] [Indexed: 12/17/2022]
Abstract
The field of vaccinology is increasingly moving toward the generation, analysis, and modeling of extremely large and complex high-dimensional datasets. We have used data such as these in the development and advancement of the field of vaccinomics to enable prediction of vaccine responses and to develop new vaccine candidates. However, the application of systems biology to what has been termed "big data," or "high-dimensional data," is not without significant challenges-chief among them a paucity of gold standard analysis and modeling paradigms with which to interpret the data. In this article, we relate some of the lessons we have learned over the last decade of working with high-dimensional, high-throughput data as applied to the field of vaccinomics. The value of such efforts, however, is ultimately to better understand the immune mechanisms by which protective and non-protective responses to vaccines are generated, and to use this information to support a personalized vaccinology approach in creating better, and safer, vaccines for the public health.
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Affiliation(s)
- Ann L Oberg
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA
| | - Brett A McKinney
- Tandy School of Computer Science, Department of Mathematics, University of Tulsa, Tulsa, OK, USA
| | - Daniel J Schaid
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA
| | - V Shane Pankratz
- UNM Health Sciences Library & Informatics Center, Division of Nephrology, University of New Mexico, Albuquerque, NM, USA
| | | | - Gregory A Poland
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.
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11
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Peptide-Based Vaccination and Induction of CD8+ T-Cell Responses Against Tumor Antigens in Breast Cancer. BioDrugs 2014; 29:15-30. [DOI: 10.1007/s40259-014-0114-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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12
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Mohit E, Hashemi A, Allahyari M. Breast cancer immunotherapy: monoclonal antibodies and peptide-based vaccines. Expert Rev Clin Immunol 2014; 10:927-61. [DOI: 10.1586/1744666x.2014.916211] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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13
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Curigliano G, Spitaleri G, Dettori M, Locatelli M, Scarano E, Goldhirsch A. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Rev Anticancer Ther 2014; 7:1225-41. [PMID: 17892423 DOI: 10.1586/14737140.7.9.1225] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cancer vaccine-based immunotherapy should potentiate immunosurveillance function, preventing and protecting against growing tumors. Tumor cells usually activate the immune system, including T lymphocytes and natural killer cells, which are able to eliminate the transformed cells. Immunosubversion mechanisms related to tumor cells antigenic immunoediting induces mechanisms of tolerance and immunoescape. This condition impairs not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes. Most trials evaluating breast cancer vaccines have been carried out in patients in the metastatic and adjuvant setting. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. We summarize the differential approaches, protein-based and cell-based vaccines, focusing on vaccines targeting HER2/neu protein. Another focus of the review is to provide the reader with future challenges in the field, taking into account both the immunological and clinical aspects to better target the goal.
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Affiliation(s)
- Giuseppe Curigliano
- European Institute of Oncology, Department of Medicine, Division of Medical Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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14
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Tang CK, Katsara M, Apostolopoulos V. Strategies used for MUC1 immunotherapy: human clinical studies. Expert Rev Vaccines 2014; 7:963-75. [DOI: 10.1586/14760584.7.7.963] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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15
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Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tsuchida A, Okajima T, Furukawa K, Urano T, Furukawa K. Trimeric Tn antigen on syndecan 1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin α5β1 and matrix metalloproteinase 9. J Biol Chem 2013; 288:24264-76. [PMID: 23814067 PMCID: PMC3745370 DOI: 10.1074/jbc.m113.455006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Revised: 06/13/2013] [Indexed: 01/12/2023] Open
Abstract
We demonstrated previously that ppGalNAc-T13 (T13), identified as an up-regulated gene with increased metastasis in a DNA microarray, generated trimeric Tn (tTn) antigen (GalNAcα1-Ser/Thr)3 on Syndecan 1 in highly metastatic sublines of Lewis lung cancer. However, it is not known how tTn antigen regulates cancer metastasis. Here, we analyzed the roles of tTn antigen in cancer properties. tTn antigen on Syndecan 1 increased cell adhesion to fibronectin in an integrin-dependent manner. Furthermore, cell adhesion to fibronectin induced phosphorylation of focal adhesion kinase and paxillin in T13-transfectant cells. In the search of Syndecan 1-interacting molecules, it was demonstrated that tTn antigen-carrying Syndecan 1 interacted with integrin α5β1 and matrix metalloproteinase 9 and that these molecules shifted to a glycolipid-enriched microdomain/rafts along with increased metastatic potential in T13-transfectant cells. We also identified a tTn substitution site on Syndecan 1, demonstrating that tTn on Syndecan 1 is essential for the interaction with integrin α5β1 as well as for the reaction with mAb MLS128. These data suggest that high expression of the ppGalNAc-T13 gene generates tTn antigen on Syndecan 1 under reduced expression of GM1, leading to enhanced invasion and metastasis via the formation of a molecular complex consisting of integrin α5β1, Syndecan 1, and MMP-9 in the glycolipid-enriched microdomain/rafts.
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Affiliation(s)
- Yasuyuki Matsumoto
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
| | - Qing Zhang
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
| | - Kaoru Akita
- the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan
| | - Hiroshi Nakada
- the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan
| | - Kazunori Hamamura
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
| | - Akiko Tsuchida
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
- the Noguchi Institute, 1-8-1 Kaga, Itabashi, Tokyo 173-0003, Japan
| | - Tetsuya Okajima
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
| | - Keiko Furukawa
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
- the Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, 1200 Matsumoto-cho, Kasugai 487-8501, Japan, and
| | - Takeshi Urano
- the Department of Biochemistry, Shimane University School of Medicine, Izumo 693-8501, Japan
| | - Koichi Furukawa
- From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan
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16
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Emens LA. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev Anticancer Ther 2012; 12:1597-611. [PMID: 23253225 PMCID: PMC3587160 DOI: 10.1586/era.12.147] [Citation(s) in RCA: 125] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.
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Affiliation(s)
- Leisha A Emens
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, 1650 Orleans Street, Room 409, Bunting Blaustein Cancer Research Building, Baltimore, MD 21231-1000, USA.
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Abstract
INTRODUCTION Success of HBV vaccines in reducing the incidence of liver cancer, and HPV vaccines in reducing preneoplastic cervical lesions, demonstrate the potential of cancer reduction by harnessing the immune system. For most human cancers, infectious etiology is not known but other tumor antigens, candidates for vaccines, have been identified. AREAS COVERED The authors discuss knowledge accumulated the last two decades on the tumor antigen MUC1 that has put it at the top of the list as an immunotherapy reagent. They examine evidence that anti-MUC1 immunity affects tumor development and prognosis. Finally, they review two decades of immunotherapy trials targeting MUC1, focusing primarily on vaccines but also adoptive antibody and T-cell therapies. EXPERT OPINION Most approaches targeting MUC1 have been immunotherapies administered to date to more than 1200 patients in clinical trials. Even though these trials focused on advanced cancer, encouraging results were reported particularly for less immunosuppressed patients. Furthermore, spontaneous anti-MUC1 immune responses are associated with better prognosis or with a reduced lifetime risk of developing MUC1+ cancers. MUC1 is abnormally expressed in over 80% of all cancers. Successfully targeting this molecule could benefit over a million patients diagnosed yearly with MUC1+ tumors just in the USA.
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Affiliation(s)
- Takashi Kimura
- University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA 15261 , USA
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18
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Florescu A, Amir E, Bouganim N, Clemons M. Immune therapy for breast cancer in 2010-hype or hope? ACTA ACUST UNITED AC 2011; 18:e9-e18. [PMID: 21331271 DOI: 10.3747/co.v18i1.623] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The identification of numerous breast cancer antigens has generated increasing enthusiasm for the application of immune-based therapies in breast malignancies. Although the use of monoclonal antibodies has revolutionized the "targeted therapy" of breast cancer, and the immunomodulatory effects of bisphosphonates continue to be evaluated, few studies to date have demonstrated widespread utility for other forms of immunotherapy. The present review assesses modern research and explores whether the hopes for immunotherapy can overcome the hype.
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Affiliation(s)
- A Florescu
- Division of Medical Oncology and Hematology, Princess Margaret Hospital, and Department of Medicine, University of Toronto, Toronto, ON
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19
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TOYOHARA YUKIYO, HASHITANI SUSUMU, KISHIMOTO HIROMITSU, NOGUCHI KAZUMA, YAMAMOTO NOBUTO, URADE MASAHIRO. Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line. Oncol Lett 2011; 2:685-691. [PMID: 22848250 PMCID: PMC3406437 DOI: 10.3892/ol.2011.306] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 04/07/2011] [Indexed: 11/06/2022] Open
Abstract
This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model.
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Affiliation(s)
- YUKIYO TOYOHARA
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
| | - SUSUMU HASHITANI
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
| | - HIROMITSU KISHIMOTO
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
| | - KAZUMA NOGUCHI
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
| | - NOBUTO YAMAMOTO
- Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA 19126-3305, USA
| | - MASAHIRO URADE
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
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20
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Abstract
The overexpression and aberrant glycosylation of MUC1 is associated with a wide variety of cancers, making it an ideal target for immunotherapeutic strategies. This review highlights the main avenues of research in this field, focusing on adenocarcinomas, from the preclinical to clinical; the problems and possible solutions associated with each approach; and speculates on the direction of MUC1 immunotherapeutic research over the next 5-10 years.
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Affiliation(s)
- Richard E Beatson
- Breast Cancer Biology Group, King's College London, Guy's Hospital, London SE1 9RT, UK
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21
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Yuan S, Shi C, Liu L, Han W. MUC1-based recombinant Bacillus Calmette-Guerin vaccines as candidates for breast cancer immunotherapy. Expert Opin Biol Ther 2010; 10:1037-48. [PMID: 20420512 DOI: 10.1517/14712598.2010.485185] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
IMPORTANCE OF THE FIELD The challenge in breast cancer vaccine development is to find the best combination of antigen, adjuvant and delivery system to produce a strong and long-lasting immune response. Mucin 1 (MUC1) is a potential candidate target for breast cancer immunotherapy. Bacillus Calmette-Guerin (BCG) is used widely in human vaccines. Furthermore, it can potentially offer unique advantages for developing a safe and effective multi-vaccine vehicle. Due to these properties, the development of MUC1 based recombinant BCG (rBCG) vaccines for breast cancer immunotherapy has gained great momentum in recent years. AREAS COVERED IN THIS REVIEW Our aim is to discuss the recent progress in MUC1-based breast cancer immunotherapy and to highlight the advantages of MUC1-based rBCG vaccines as the new breast cancer vaccines. WHAT THE READER WILL GAIN Several promising MUC1-based rBCG vaccines have been shown to induce MUC1-specific antitumor immune responses in pre-clinical studies. This review updates and evaluates this very important and rapidly developing field, and provides a critical perspective and information source for its potential clinical applications. TAKE HOME MESSAGE MUC1-based rBCG vaccines have been shown to elicit an effective anti-tumor immune response in vivo demonstrating its potential utility in breast cancer treatment.
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Affiliation(s)
- Shifang Yuan
- Fourth Military Medical University, Xijing Hospital, Department of Vascular and Endocrine Surgery, Xi'an, 710032, People's Republic of China.
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22
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Adams MM, Damani P, Perl NR, Won A, Hong F, Livingston PO, Ragupathi G, Gin DY. Design and synthesis of potent Quillaja saponin vaccine adjuvants. J Am Chem Soc 2010; 132:1939-45. [PMID: 20088518 PMCID: PMC2820154 DOI: 10.1021/ja9082842] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that significantly enhances the immune response to a coadministered antigen. Only a handful of adjuvants have both sufficient potency and acceptable toxicity for clinical investigation. One promising adjuvant is QS-21, a saponin natural product that is the immunopotentiator of choice in many cancer and infectious disease vaccine clinical trials. However, the therapeutic promise of QS-21 adjuvant is curtailed by several factors, including its scarcity, difficulty in purification to homogeneity, dose-limiting toxicity, and chemical instability. Here, we report the design, synthesis, and evaluation of chemically stable synthetic saponins. These novel, amide-modified, non-natural substances exhibit immunopotentiating effects in vivo that rival or exceed that of QS-21 in evaluations with the GD3-KLH melanoma conjugate vaccine. The highly convergent synthetic preparation of these novel saponins establishes new avenues for discovering improved molecular adjuvants for specifically tailored vaccine therapies.
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Affiliation(s)
- Michelle M. Adams
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Payal Damani
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Nicholas R. Perl
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Annie Won
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Feng Hong
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Philip O. Livingston
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - Govind Ragupathi
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
| | - David Y. Gin
- Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
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23
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Kokowski K, Harnack U, Dorn DC, Pecher G. Quantification of the CD8+ T cell response against a mucin epitope in patients with breast cancer. Arch Immunol Ther Exp (Warsz) 2008; 56:141-5. [PMID: 18373244 PMCID: PMC2766492 DOI: 10.1007/s00005-008-0011-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Accepted: 01/25/2008] [Indexed: 01/28/2023]
Abstract
Introduction: Mucin 1, encoded by the MUC1 gene, is a tumor-associated antigen expressed on the surface of breast cancer cells. It would be of interest to see whether there is a naturally existing T cell immune response against mucin epitopes in cancer patients. Materials and Methods: Using tetramer and interferon-γ assays, the immune response to one MUC1 peptide epitope in the peripheral blood of breast cancer patients was quantified. The data were compared with the clinical course of the patients. Results: CD8+ T cells capable of recognizing the HLA-A*0201-restricted STAPPVHNV epitope were detected in 9 of 19 patients with a frequency ranging 0.01–0.082%. No significant difference was found between the occurrence of epitope-specific CD8+ T cells of patients with progressive disease and disease-free patients. However, all patients with stable disease showed a specific immune response, including both patients with the highest frequency. Conclusions: The results of this study provide further evidence that a natural specific cellular immune response against this mucin epitope exists in breast cancer patients.
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Affiliation(s)
- Konrad Kokowski
- Medical Clinic of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Ulf Harnack
- Medical Clinic of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - David C. Dorn
- Medical Clinic of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
- Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, 10021 NY USA
| | - Gabriele Pecher
- Medical Clinic of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
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24
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Yamamoto N, Suyama H, Yamamoto N, Ushijima N. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer 2008; 122:461-7. [PMID: 17935130 DOI: 10.1002/ijc.23107] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Patient serum Nagalase activity is proportional to tumor burden. The deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation and immunosuppression. Stepwise incubation of purified Gc protein with immobilized beta-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages treated in vitro with GcMAF (100 pg/ml) are highly tumoricidal to mammary adenocarcinomas. Efficacy of GcMAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of GcMAF (100 ng). As GcMAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase. Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of GcMAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of GcMAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years.
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Affiliation(s)
- Nobuto Yamamoto
- Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA 19126-3305, USA.
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25
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Curigliano G, Rescigno M, Goldhirsch A. Immunology and breast cancer: therapeutic cancer vaccines. Breast 2007; 16 Suppl 2:S20-6. [PMID: 17706425 DOI: 10.1016/j.breast.2007.07.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Cancer immunosurveillance is a process that results from activity of recognition and destruction of cancer cells by innate and adaptive immune effector cells and molecules. Cancer cells can avoid immunosurveillance through the immunoselection, that is the development of poorly immunogenic tumor-cell variants, and through subversion of the immune system (also known as immunosubversion). Identification of tumor antigens (Ags) that can be recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. Breast cancer vaccines can induce immunogenic response against tumors weakly immunogenic; usually have a good tolerance and safety profile and can induce a long-term immune memory, critical to prevent efficiently tumor recurrence. Several studies evaluating breast cancer vaccines have been performed in patients with extended metastatic breast cancer, usually refractory to other standard treatments so that clinical efficacy was difficult to achieve. Significant immune responses against tumor Ags induced upon vaccinations were described to several tumor Ag vaccines. A better understanding of the relation between innate and adaptive immune responses, of the immune escape mechanisms employed by tumor cells and acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumor growth are necessary for leading to a more comprehensive immunotherapeutic approach in breast cancer.
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Affiliation(s)
- Giuseppe Curigliano
- Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy.
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Abstract
The genomic revolution has advanced our understanding of breast cancer biology and the molecular basis of antitumor immunity. Trastuzumab, the first monoclonal antibody for breast cancer, is now a routine part of clinical care. Breast cancer vaccines may be more effective by actively recruiting both humoral and cellular immunity to the therapeutic effort. However, immunization alone is unlikely to have significant activity against established breast cancers, where it is limited by potent mechanisms of immune tolerance and the immunobiology of breast cancer itself. The next generation of clinical studies should integrate breast cancer vaccines with standard breast cancer drugs or novel immunotherapeutics in strategic doses and schedules that abrogate immune tolerance and groom the tumor microenvironment for a productive immune response.
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Affiliation(s)
- Leisha A Emens
- Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 4M90, Baltimore, MD 21231-1000, USA.
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Mitchell MS, Lund TA, Sewell AK, Marincola FM, Paul E, Schroder K, Wilson DB, Kan-Mitchell J. The cytotoxic T cell response to peptide analogs of the HLA-A*0201-restricted MUC1 signal sequence epitope, M1.2. Cancer Immunol Immunother 2007; 56:287-301. [PMID: 16874487 PMCID: PMC11029875 DOI: 10.1007/s00262-006-0191-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2005] [Accepted: 06/01/2006] [Indexed: 11/26/2022]
Abstract
The mucin MUC1 molecule is overexpressed on a variety of adenocarcinomas and is thus, a potential target for immunotherapy. Of the MUC1 peptides that bind to HLA-A*0201(A2), M1.2 (LLLLTVLTV) from the signal sequence appears to be the most immunogenic in humans. Here we have shown that large numbers (10(9)) of tetramer-binding M1.2-specific cytotoxic T lymphocytes (CTL) can be generated ex vivo from circulating precursors, derived from healthy adults. However, there was significant interpersonal variation in the level of co-stimulatory signal required. Tetramer-binding cells also required maturation in culture to become proficient killers of the HLA-A2(+) MUC1(+) MCF7 cell line, known to express a low number of endogenously processed M1.2. The functional avidity of M1.2-specific CTL, however, was low as compared to CTL specific for an HIV-1 epitope. Despite the low avidity, M1.2-specific CTL were polyfunctional, secreting multiple cytokines upon degranulation with antigen recognition. To identify potential agonist peptides that may be superior immunogens, an M1.2-specific CTL culture was used to scan a large nonameric combinatorial peptide library. Of 54 predicted peptides, 4 were "consensus" agonists because they were recognized by CTL from two other donors. Two agonists, p29 (LLPWTVLTV) and p15 (VLLWTVLTV), were equally stimulatory when loaded onto C1R target cells transfected with wild-type HLA-A2. Both agonists induced IL-2, TNF-alpha, IFN-gamma, and degranulation with M1.2-specific CTL. In contrast, production of these cytokines, which are tightly regulated by specific activation through the T cell receptor, was restricted when the CTL were stimulated with peptides loaded onto C1R cells that were transfected with an HLA-A2 molecule bearing a mutation that abrogates binding to the CD8 co-receptor. Thus, activation by both M1.2 and its agonists was dependent upon CD8, showing that compensation by the co-receptor was necessary for the human T cell response to M1.2.
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Affiliation(s)
- Malcolm S. Mitchell
- Department of Medicine, Wayne State University School of Medicine, Detroit, MI 48201 USA
- Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201 USA
- Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201 USA
| | - Teri A. Lund
- Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201 USA
| | - Andrew K. Sewell
- T Cell Modulation Group, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Francesco M. Marincola
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892 USA
| | - Elyse Paul
- Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201 USA
| | - Kim Schroder
- Torrey Pines Institute for Molecular Studies, La Jolla, CA USA
| | - Darcy B. Wilson
- Torrey Pines Institute for Molecular Studies, La Jolla, CA USA
| | - June Kan-Mitchell
- Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201 USA
- Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201 USA
- Present Address: Hudson-Webber Cancer Research Center, Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI 48201 USA
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Abstract
Improvement in survival among patients with early malignancy is well established in various cancers. However, long-term survival in those with advanced malignancy has changed little and this poses a major therapeutic challenge to clinicians. Anti-cancer immunotherapy is a novel approach, which is still experimental, but offers a new therapeutic strategy. In this review, we discuss the basic immunological interplay between the host immune system and the tumour, mechanisms of anti-tumour immune responses induced by immunotherapy and key in vivo pilot studies of active specific immunotherapy in various sold cancers, carried out during the last five years.
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Affiliation(s)
- M M Aloysius
- Section of Surgery, Nottingham University Hospitals, Queen's Medical Centre, UK.
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29
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Li D, Li H, Zhang P, Wu X, Wei H, Wang L, Wan M, Deng P, Zhang Y, Wang J, Liu Y, Yu Y, Wang L. Heat shock fusion protein induces both specific and nonspecific anti-tumor immunity. Eur J Immunol 2006; 36:1324-36. [PMID: 16619287 DOI: 10.1002/eji.200535490] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Mucin 1 (MUC1) is a tumor antigen, and the most important epitopes that can induce cytotoxic T lymphocytes (CTL) reside in the variable-number tandem repeats (VNTR). Heat shock protein (HSP) complexes isolated from tumors have been shown to induce specific anti-tumor immunity. HSP alone can also induce nonspecific immunity. To explore the possibility to utilize the specific anti-tumor immunity induced by MUC1 VNTR and the nonspecific immunity induced by HSP, we constructed a recombinant protein (HSP65-MUC1) by fusing Bacillus Calmette-Guérin-derived HSP65 with the MUC1 VNTR peptide and tested its ability to induce anti-tumor activities in a tumor challenge model. The growth of MUC1-expressing tumors was significantly inhibited in mice immunized with HSP65-MUC1, both before and after tumor challenge. A much larger percentage of immunized mice survived the tumor challenge than non-immunized mice. Correlating with the anti-tumor activity, HSP65-MUC1 was shown to induce MUC1-specific CTL as well as nonspecific anti-tumor immunity. In the human system, HSP65-MUC1-loaded human DC induced the generation of autologous MUC1-specific CTL in vitro. These results suggest that exogenously applied HSP65-MUC1 may be used to treat MUC1 tumors by inducing the epitope-specific CTL as well as nonspecific anti-tumor responses mediated by the HSP part of the fusion protein.
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Affiliation(s)
- Dapeng Li
- Department of Molecular Biology, Jilin University, Changchun, China
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30
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Gückel B, Rentzsch C, Nastke MD, Marmé A, Gruber I, Stevanović S, Kayser S, Wallwiener D. Pre-existing T-cell immunity against mucin-1 in breast cancer patients and healthy volunteers. J Cancer Res Clin Oncol 2005; 132:265-74. [PMID: 16374613 DOI: 10.1007/s00432-005-0064-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2005] [Accepted: 11/11/2005] [Indexed: 01/28/2023]
Abstract
PURPOSE There is evidence that some tumor patients are able to generate tumor-associated antigen (TAA)-specific T-cell immunity spontaneously. However, little is understood about the existence and nature of self-reactive T-cells that recognize TAA in healthy donors (HD). METHODS Human mucin (MUC-1), a highly glycosylated transmembrane protein, is a well characterized TAA expressed by epithelial tumors. We compared endogenous MUC-1-specific T-cell immunity of breast cancer patients (BCP) and healthy volunteers using two MUC-1-derived HLA-A*0201-restricted peptides (MUC-1(950-958), MUC-1(12-20)). Antigen-dependent interferon (IFN)-gamma and Granzyme B expression of T-cells were analysed by a reverse transcription-polymerase chain reaction (qRT-PCR)-based assay. RESULTS A 32% of BCP and 43% of healthy volunteers revealed pre-existent CD8+ T-cells specific for MUC-1(950-958) but not for MUC-1(12-20). In patients, MUC-1-specific T-cells have been detected mainly in early stage disease prior adjuvant therapy. Those T-cells showed MUC-1-dependent IFN-gamma production after short-term stimulation but no clear Granzyme B expression. However, after repetitive in vitro stimulations using peptide-pulsed CD40-stimulated B-cell lines as autologous antigen presenting cells (APC) T-cell lines exhibited lytic capacity against HLA-A*0201+/MUC-1+ tumor cells. CONCLUSION MUC-1(950-958) is a dominant tumor antigen against which CD8+ T-cells were found frequently in BCP as well as in HD. Until now, this was only known for MelanA/MART-1. In contrast to previous reports, MUC-1-specific immunity was not linked to gender or number of pregnancies in women. Whether MUC-1(950-958)-related immunity highlights a yet unknown cross-reactivity in HD remains unclear. The presence of MUC-1-specific T-cells in some BCP may reflect a balance between immune tolerance and immune defence during aetiopathology.
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Affiliation(s)
- Brigitte Gückel
- Department of Obstetrics and Gynecology, University of Tübingen, Calwerstrasse 7, 72076, Tübingen, Germany.
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31
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Curigliano G, Spitaleri G, Pietri E, Rescigno M, de Braud F, Cardillo A, Munzone E, Rocca A, Bonizzi G, Brichard V, Orlando L, Goldhirsch A. Breast cancer vaccines: a clinical reality or fairy tale? Ann Oncol 2005; 17:750-62. [PMID: 16293674 DOI: 10.1093/annonc/mdj083] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The characterization of tumor antigens recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. The potential advantages of the vaccines are: (i) the induction of a robust immune response against tumors that are spontaneously weekly immunogenic; (ii) the tumor specificity for some antigens; (iii) the good tolerance and safety profile and (iv) the long-term immune memory, critical to prevent efficiently tumor recurrence. Most trials evaluating breast cancer vaccines have been carried out in patients with extended metastatic breast cancer, characterized by aggressive tumors, resistant to standard cytotoxic treatments, so that clinical efficacy was difficult to achieve. However, some significant immune responses against tumor antigens induced upon vaccinations were recorded. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. Data of clinical activity have been observed by using vaccines targeting HER2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen and carbohydrate antigen given after stem cell rescue. The review discusses possible future directions for vaccine development and applications in the adjuvant setting.
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Affiliation(s)
- G Curigliano
- Department of Medicine, Clinical Pharmacology and New Drugs Development Unit, Division of Experimental Oncology, Laboratory of Experimental Immunology, European Institute of Oncology, Milan, Italy.
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32
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Guo BL, Liu Z, Aldrich WA, Lopez RD. Innate Anti-breast Cancer Immunity of Apoptosis-resistant Human γδ-T cells. Breast Cancer Res Treat 2005; 93:169-75. [PMID: 16187237 DOI: 10.1007/s10549-005-4792-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We previously identified a CD2-initiated signaling pathway which inhibits activation-induced cell death in mitogen-stimulated human gammadelta-T cells permitting the large-scale expansion of these cells. Here we report the innate anti-tumor activity of expanded human gammadelta-T cells against human breast cancer cells. Apoptosis-resistant human gammadelta-T cells which were expanded in vitro from cultured human peripheral blood mononuclear cells displayed lytic activity against breast cancer cell lines MDA-MB-231, MCF-7 and T-47D, but failed to kill normal human skin fibroblasts and normal human liver cells. Monoclonal antibodies (mAb) directed against the gammadelta-T cell receptor (TCR) or mAb directed against either the Vgamma9 or the Vdelta2 TCR chains were able to block gammadelta-T cell-mediated lysis of MDA-MB-231 cells. In addition, mAb against intercellular adhesion molecules-1 (ICAM-1/CD54) or CD18 (beta subunit of ICAM-1 counter-receptor) also blocked gammadelta-T cell-mediated killing of MDA-MB-231 cells. Ex vivo expanded human gammadelta-T cells are thus able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner; ICAM-1 and CD18 also appear to be involved in the interactions between sensitive breast cancer cells and cytolytic gammadelta-T cells. As apoptosis-resistant human gammadelta-T cells can now readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses for the primary or adjuvant treatment of breast cancer.
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Affiliation(s)
- Ben L Guo
- Bone Marrow Transplantation Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Yuan SF, Li KZ, Wang L, Dou KF, Yan Z, Han W, Zhang YQ. Expression of MUC1 and its significance in hepatocellular and cholangiocarcinoma tissue. World J Gastroenterol 2005; 11:4661-6. [PMID: 16094706 PMCID: PMC4615407 DOI: 10.3748/wjg.v11.i30.4661] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relation between MUC1 expression, distribution, and prognosis in hepatocellular and cholangiocarcinoma (HCC and CC) and cirrhotic liver tissues, and their significance in HCC and CC diagnosis.
METHODS: Expression and distribution of MUC1 were examined by immunohistochemical assay with anti-MUC1 mAb in 59 samples of HCC and 37 samples of CC, 20 samples of cirrhotic liver tissues, and 10 samples of normal liver tissues, seeking possible associations between MUC1 positive expression, distribution in HCC and CC (primary liver cancer, PLC) cases and the studied clinical data.
RESULTS: Immunohistochemical analysis of MUC1 expression showed that in the 96 PLC samples, 68 (70.8%) were strong positive, and 6 (6.2%) were weak positive. Only 4 in the 20 cirrhotic liver tissues were found to be weak positive, while no expression of MUC1 was detected in normal liver tissues. Apparently, the high expression rate of MUC1 in PLC tissues was statistically significant in comparison to that in cirrhotic and normal liver tissues. The expressed MUC1 protein, stained in dark brownish or brownish-yellow particles, chiefly localized on the cancer cell membranes or in cytoplasm. In the 68 strong positive samples, 40 were detected on cell membrane and the other 28 were in cytoplasm. In addition, follow-up studies of those PLC cases demonstrated that MUC1 expression on cell membrane or in cytoplasm was closely associated with PLC prognosis. The expression of MUC1 in PLC had little statistical significance in respect of the pathological types and sizes of the tumors, but a strong relationship regarding histological differentiation, metastasis of lymph nodes, portal canal emboli, and post-operational recurrence of the carcinomas. After 3 years of tumor excision, the metastasis rate in MUC1 positive expression group (67.6%) was much higher than that in MUC1 weak expression group (33.3%) and negative expression group (31.8%), and thus the survival rate in MUC1-positive expression group was significantly different from that in weak and negative expression groups.
CONCLUSION: Expression and localization of MUC1 proteins in primary liver carcinomas (PLCs) may act as prognostic markers, and MUC1 molecules might be helpful in differential diagnosis.
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Affiliation(s)
- Shi-Fang Yuan
- Department of Vascular and Endocrine Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
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Abstract
A growing body of evidence supports crucial roles for glycans at various pathophysiological steps of tumour progression. Glycans regulate tumour proliferation, invasion, haematogenous metastasis and angiogenesis, and increased understanding of these roles sets the stage for developing pharmaceutical agents that target these molecules. Such novel agents might be used alone or in combination with operative and/or chemoradiation strategies for treating cancer.
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Affiliation(s)
- Mark M Fuster
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California, 92093-0687, USA
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35
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Abstract
One approach in the immunotherapy of cancer patients involves vaccination with peptides derived from tumour-associated antigens specifically designed to associate with T cells in the context of major histocompatibility complex (MHC) class I or II molecules. Several clinical trials in different tumour types have been conducted utilising this vaccination strategy. The majority of trials indicate that peptide vaccination has few toxicities associated with its administration, but disparities exist between in vitro and clinical responses. However, this represents an evolving field and, thus, it is difficult to draw firm conclusions concerning the efficacy of peptide-based vaccines for cancer immunotherapy. Improvements to peptide vaccination, including the addition of various adjuvants, the utilisation of peptide-pulsed dendritic cells, multipeptide vaccinations, the addition of helper peptides and peptide delivery through the use of mini-genes, are encouraging and serve as important guides for future research.
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Affiliation(s)
- Joeli A Brinkman
- University of Southern California, 1501 San Pablo Street, ZNI 245, MC 2821, Los Angeles, CA 90089-2821, USA
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Correa I, Plunkett T, Coleman J, Galani E, Windmill E, Burchell JM, Taylor-Papdimitriou J. Responses of human T cells to peptides flanking the tandem repeat and overlapping the signal sequence of MUC1. Int J Cancer 2005; 115:760-8. [PMID: 15729696 DOI: 10.1002/ijc.20949] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The epithelial mucin MUC1 is one of the few tumour-associated antigens identified for breast cancer. Several MUC1-derived peptides binding HLA-A*0201 molecules have been identified that correspond to sequences outside the tandem repeat. Immunisation with some of these peptides induces protective antitumour immunity in mice. Another HLA-A*0201-binding peptide has been identified in a human system. We have evaluated the CD8(+) T-cell responses to all these peptides using peripheral blood lymphocytes from breast cancer patients and normal donors. Specific CD8(+) T-cell responses could be generated in vitro against some of these peptides but only after several rounds of in vitro restimulation, and they did not recognise human cells endogenously expressing the antigen. Nevertheless, T cells recognised by HLA-A*0201 tetramers carrying a peptide from the signal sequence (LLLLTVLTV) could be detected in the peripheral blood of some HLA-A*0201(+) breast cancer patients but not in healthy adults. This peptide is the only one of those tested which was identified in the human system, and the results emphasize the potential problems involved in translation of data from laboratory animal models to the human system.
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Affiliation(s)
- Isabel Correa
- Breast Cancer Biology Group, Cancer Research UK, Guy's Hospital, London, United Kingdom
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37
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Abstract
The great majority of cancer patients can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on the antigenic epitope and vaccine design. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H and the mucin backbone MUC1, and cancer cells expressing these antigens. Other antigens required additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against tumor cells than the unmodified antigens. Tn, sTn and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer cell surface. The optimal approach for Le(Y), KSA, PSMA, and CA125 (MUC16) remains to be determined. Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required due to tumor cell heterogeneity, heterogeneity of the human immune response and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, Phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.
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Affiliation(s)
- Govind Ragupathi
- Laboratory of Tumor Vaccinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City New York, USA
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Narayanan K, Jaramillo A, Benshoff ND, Campbell LG, Fleming TP, Dietz JR, Mohanakumar T. Response of established human breast tumors to vaccination with mammaglobin-A cDNA. J Natl Cancer Inst 2004; 96:1388-96. [PMID: 15367572 DOI: 10.1093/jnci/djh261] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND A novel breast cancer-associated antigen, mammaglobin-A, is expressed in 80% of primary breast tumors. The characterization of immune responses against this highly expressed breast cancer-specific antigen would be of value in the development of new therapeutic strategies for breast cancer. METHODS We developed an in vivo model using human leukocyte antigen-A*0201/human CD8+ (HLA-A2+/hCD8+) double-transgenic mice to define the epitopes and to study the level of protection acquired by mammaglobin-A cDNA vaccination toward mammaglobin-A+/HLA-A2+ breast cancer cell lines. Mammaglobin-A epitopes were identified using an HLA class I peptide binding prediction computer program, and their activity was verified using gamma interferon ELISPOT and cytotoxicity assays. RESULTS We identified seven mammaglobin-A-derived candidate epitopes that bind the HLA-A*0201 molecule (Mam-A2.1-7). CD8+ cytotoxic T lymphocytes (CTLs) from HLA-A2+/hCD8+ mice reacted to the Mam-A2.1 (amino acids [aa] 83-92, LIYDSSLCDL), Mam-A2.2 (aa 2-10, KLLMVLMLA), Mam-A2.4 (aa 66-74, FLNQTDETL), and Mam-A2.6 (aa 32-40, MQLIYDSSL) epitopes. CD8+ CTLs from breast cancer patients also recognized a similar epitope pattern as did those in the HLA-A2+/hCD8 mice and reacted to the Mam-A2.1, Mam-A2.2, Mam-A2.3, Mam-A2.4, and Mam-A2.7 epitopes. Passive transfer of mammaglobin-A-reactive CTLs into SCID (severe combined immunodeficient) beige mice with actively growing mammaglobin-A+ tumors resulted in statistically significant regression (P<.001) in the growth of the tumors. CONCLUSIONS The HLA-A2+/hCD8+ mouse represents a valuable animal model to characterize the HLA-A*0201-restricted CD8+ CTL immune response to mammaglobin-A in vivo, and the data reported here demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and/or prevention of breast cancer.
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Affiliation(s)
- Kishore Narayanan
- Department of Surgery, Washington University School of Medicine, Box 8109-3328, CSRB, 660 S. Euclid Ave., St. Louis, MO, 63110, USA
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Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ. MUC1 immunobiology: from discovery to clinical applications. Adv Immunol 2004; 82:249-93. [PMID: 14975259 DOI: 10.1016/s0065-2776(04)82006-6] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Anda M Vlad
- Department of Immunology, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15261, USA
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40
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Croce MV, Isla-Larrain MT, Demichelis SO, Gori JR, Price MR, Segal-Eiras A. Tissue and serum MUC1 mucin detection in breast cancer patients. Breast Cancer Res Treat 2004; 81:195-207. [PMID: 14620915 DOI: 10.1023/a:1026110417294] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tumor MUC1 expression as well as levels of MUC1, MUC1 circulating immune complexes (MUC1-CIC) and free antibodies against MUC1 (IgG and IgM-MUC1) were evaluated in 70 breast cancer patients with different stages of disease. Controls included: 135 serum samples from healthy women, normal mammary tissue samples (n = 7) and benign breast disease specimens (n = 6). In all assays, pre- and post-vaccination serum samples from breast cancer patients belonging to a vaccination protocol developed at the Memorial Sloan Kettering Cancer Center (New York, USA) were included as controls. Serum MUC1 was measured through Cancer Associated Serum Antigen test and CA15-3 test. Employing ELISA, MUC1-CIC-IgG/M were measured with either C595 or SM3 monoclonal antibodies (MAb) as catchers and also free antibodies against MUC1 (IgG and IgM) using 100mer peptide as catcher. Employing multivariate statistical analysis, results were correlated with age, tumor type, stage of disease and grade of differentiation. By quantitative immunohistochemistry using three anti-MUC1 core protein MAbs (C595, HMFG2 and SM3), tumor MUC1 was detected in 60/70 (86%) breast cancer specimens which reacted with at least one of these MAbs. High MUCI serum levels were detected in 14/67 (21%); IgG and IgM anti-MUC1 antibodies were found elevated in 32 and 14%, respectively, while IgG-MUC1-CIC-measured with C595 in 42% and IgM-MUC1-CIC in 54%; finally, SM3 was positive in 43 and 18%, respectively. Results of these studies demonstrate that in a group of breast cancer patients, MUC1 was detected both in tissue specimens as well as free in serum samples; furthermore, MUC1 can also circulate complexed with IgG and IgM antibodies; thus an accurate measurement should include free and complexed forms. On the other hand, immunohistochemical studies on breast cancer tissues may contribute to reveal different MUC1 glycoforms.
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MESH Headings
- Adenocarcinoma/blood
- Adenocarcinoma/metabolism
- Adult
- Aged
- Aged, 80 and over
- Antigen-Antibody Complex/immunology
- Antigens, Neoplasm/immunology
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/blood
- Breast Neoplasms/metabolism
- Female
- Humans
- Immunoglobulin G/analysis
- Immunoglobulin M/analysis
- Middle Aged
- Mucin-1/blood
- Mucin-1/immunology
- Mucin-1/metabolism
- Neoplasms, Ductal, Lobular, and Medullary/blood
- Neoplasms, Ductal, Lobular, and Medullary/metabolism
- Tissue Distribution
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Affiliation(s)
- María V Croce
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas, Facultad de Ciencias Médicas, UNLP La Plata, Argentina
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Pantuck AJ, van Ophoven A, Gitlitz BJ, Tso CL, Acres B, Squiban P, Ross ME, Belldegrun AS, Figlin RA. Phase I Trial of Antigen-Specific Gene Therapy Using a Recombinant Vaccinia Virus Encoding MUC-1 and IL-2 in MUC-1-Positive Patients With Advanced Prostate Cancer. J Immunother 2004; 27:240-53. [PMID: 15076142 DOI: 10.1097/00002371-200405000-00009] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
MUC-1 is overexpressed on many tumor cells. In addition, aberrant glycosylation of MUC-1 on human tumors leads to exposure of cryptic peptide epitopes that play a role in tumor immunity. As such, it has been identified as a potential target for immunotherapy. The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose, safety of a multiple-dose regimen, and the immunologic effect of vaccinia virus expressing MUC-1 and IL-2 genes (VV/MUC-1/IL-2) in patients with advanced prostate cancer. Five x 10(5), 5 x 10(6), and 5 x 10(7) plaque-forming units (pfu) of vaccinia viruses were used in the dose-escalating study. Viruses were given via intramuscular injection, and clinical response and immune function modulation were analyzed. No grade 3 or 4 toxicity was observed. Objective clinical response was observed after the fourth injection (0.3 ng/mL) in only one patient who received an intermediate dose of virus. Systemic immune modulation in this patient included (1) up-regulation of IL-2 (CD25) and T cell (TcR alphabeta) receptors, (2) increase in the CD4/CD8 ratio (2.5-fold) (3) augmentation of T-helper type 1 cell (TH1) (interferon-gamma and tumor necrosis factor-alpha) but not TH2 (IL-4) cytokine mRNA expression, (4) induction of natural killer cell activity and MHC independent MUC-1 specific cytotoxic T-cell activity, and (5) normalization of mRNA expression of T-cell-associated signal transduction molecules TcR-zeta and p56lck. These results suggest that VV/MUC-1/IL-2 gene therapy with a maximum tolerated dose of 5 x 10(7) pfu is safe and well tolerated.
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Affiliation(s)
- Allan J Pantuck
- Department of Urology, David Geffen School of Medicine at University of California, Los Angeles 90095, USA
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Affiliation(s)
- Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
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Grinstead JS, Schuman JT, Campbell AP. Epitope Mapping of Antigenic MUC1 Peptides to Breast Cancer Antibody Fragment B27.29: A Heteronuclear NMR Study†. Biochemistry 2003; 42:14293-305. [PMID: 14640698 DOI: 10.1021/bi0301237] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
MUC1 mucin is a breast cancer-associated transmembrane glycoprotein, of which the extracellular domain is formed by the repeating 20-amino acid sequence GVTSAPDTRPAPGSTAPPAH. In neoplastic breast tissue, the highly immunogenic sequence PDTRPAP (in bold above) is exposed. Antibodies raised directly against MUC1-expressing tumors offer unique access to this neoplastic state, as they represent immunologically relevant "reverse templates" of the tumor-associated mucin. In a previous study [Grinstead, J. S., et al. (2002) Biochemistry 41, 9946-9961], (1)H NMR methods were used to correlate the effects of cryptic glycosylation outside of the PDTRPAP core epitope sequence on the recognition and binding of Mab B27.29, a monoclonal antibody raised against breast tumor cells. In the study presented here, isotope-edited NMR methods, including (15)N and (13)C relaxation measurements, were used to probe the recognition and binding of the PDTRPAP epitope sequence to Fab B27.29. Two peptides were studied: a one-repeat MUC1 16mer peptide of the sequence GVTSAPDTRPAPGSTA and a two-repeat MUC1 40mer peptide of the sequence (VTSAPDTRPAPGSTAPPAHG)(2). (15)N and (13)C NMR relaxation parameters were measured for both peptides free in solution and bound to Fab B27.29. The (13)C(alpha) T(1) values best represent changes in the local correlation time of the peptide epitope upon binding antibody, and demonstrate that the PDTRPAP sequence is immobilized in the antibody-combining site. This result is also reflected in the appearance of the (15)N- and (13)C-edited HSQC spectra, where line broadening of the same peptide epitope resonances is observed. The PDTRPAP peptide epitope expands upon the peptide epitope identified previously in our group as PDTRP by homonuclear NMR experiments [Grinstead, J. S., et al. (2002) Biochemistry 41, 9946-9961], and illustrates the usefulness of the heteronuclear NMR experiments. The implications of these results are discussed within the context of MUC1 breast cancer vaccine design.
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Affiliation(s)
- Jeffrey S Grinstead
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195, USA
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Abstract
Following vaccination with defined tumor antigens that are recognized by T cells, a small proportion of cancer patients display tumor regressions. Several reports describe anti-vaccine T-cell responses, evaluated with a variety of methods, for example, by assessing T-cell function or expression of specific TCR. However, a correlation between these T-cell responses and the tumor regressions has not yet been established. It appears that some patients display tumor regression with an unexpectedly low frequency of anti-vaccine T cells.
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Affiliation(s)
- Pierre G Coulie
- Cellular Genetics Unit, Christian de Duve Institute of Cellular Pathology, Université de Louvain, Avenue Hippocrate 74, UCL 7459, B-1200 Brussels, Belgium.
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Miles D, Papazisis K. Rationale for the clinical development of STn-KLH (Theratope) and anti-MUC-1 vaccines in breast cancer. Clin Breast Cancer 2003; 3 Suppl 4:S134-8. [PMID: 12620150 DOI: 10.3816/cbc.2003.s.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mucin-1 (MUC-1) is a high-molecular-weight glycoprotein rich in serine and threonine residues that are O-glycosylated. Expression of MUC-1 is increased in breast, ovarian, and other adenocarcinomas, and altered glycosylation results in exposure of novel peptide epitopes and the expression of tumor-associated carbohydrate residues, such as Thomsen-Freidenreich and sialyl-Tn (STn) antigens. Preclinical studies suggested that induction of immune response to tumor-associated carbohydrate moieties results in inhibition of tumor growth. A synthetic STn-keyhole limpet hemocyanin (KLH) vaccine (Theratope) is currently being evaluated in clinical trials as active specific immunotherapy in the treatment of advanced breast cancer. Two phase II trials in 50 breast cancer patients compared the STn-KLH vaccine with and without a single low-dose infusion of cyclophosphamide used as an immunomodulator prior to initiation of treatment. Humoral immune responses were higher in patients who had received low-dose cyclophosphamide intravenously (I.V.) compared with patients who had received no cyclophosphamide or oral cyclophosphamide. There was a statistically significant survival difference between all patients treated with the STn-KLH vaccine (overall median survival, 19.1 months; n = 50) and the retrospective control patients (overall median survival, 9.2 months; n = 104). Furthermore, patients who received cyclophosphamide I.V. prior to the STn-KLH vaccine had median survival rates close to 3 times that of patients in a retrospective, frequency-matched, control group who received conventional therapies (cyclophosphamide-I.V. group, 26.5 months vs. 9.2 months, control group). The trials reported minimal toxicity profile with local reactions in the injection site and some flu-like symptoms. On the basis of the phase II trial results, a phase III clinical trial of the STn-KLH vaccine is underway. The trial was closed to enrollment in March 2001 with the accrual of 1030 women. The final analysis is event driven and is expected to commence mid 2003.
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Affiliation(s)
- David Miles
- ICRF Clinical Oncology Unit, Guy's Hospital, London, UK.
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Davis ID, Jefford M, Parente P, Cebon J. Rational approaches to human cancer immunotherapy. J Leukoc Biol 2003; 73:3-29. [PMID: 12525559 DOI: 10.1189/jlb.0502261] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Over most of the 20th century, immunotherapy for cancer was based on empiricism. Interesting phenomena were observed in the areas of cancer, infectious diseases, or transplantation. Inferences were made and extrapolated into new approaches for the treatment of cancer. If tumors regressed, the treatment approaches could be refined further. However, until the appropriate tools and reagents were available, investigators were unable to understand the biology underlying these observations. In the early 1990s, the first human tumor T cell antigens were defined and dendritic cells were discovered to play a pivotal role in antigen presentation. The current era of cancer immunotherapy is one of translational research based on known biology and rationally designed interventions and has led to a rapid expansion of the field. The beginning of the 21st century brings the possibility of a new era of effective cancer immunotherapy, combining rational, immunological treatments with conventional therapies to improve the outcome for patients with cancer.
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Affiliation(s)
- Ian D Davis
- Ludwig Institute for Cancer Research, Austin & Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.
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Abstract
Reports of novel developments in tumor vaccines that have appeared in the year ending May 1, 2002 are reviewed here. Antigenic moieties were revealed for tumors previously considered nonimmunogenic. The use of peptides spanning mutations detected exclusively in tumor tissue avoids the common concern for autoimmune responses. Carbohydrate biology is revealing novel antigenic moieties. The search for helper epitopes from tumor antigens has come into full swing. Humoral immunity is regaining terrain, particularly through the development of antiidiotypic antibodies. Major steps forward have been made in optimizing modes and routes of antigen delivery and in the use of immune adjuvants. In the clinic, phase I/II trials support the notion that tumor vaccines are safe. Because these trials are conducted in patients in whom tumor remission is not a realistic endpoint, patient responses were established by immune monitoring strategies to detect subtle changes in antitumor reactivity. Both clinical and laboratory data stress the vast potential of tumor vaccines for the treatment of cancer.
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Affiliation(s)
- I Caroline Le Poole
- Cardinal Bernardin Cancer Center, Cancer Immunology Program, Loyola University, Chicago, Illinois, USA
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Fattorossi A, Battaglia A, Malinconico P, Stoler A, Andreocci L, Parente D, Coscarella A, Maggiano N, Perillo A, Pierelli L, Scambia G. Constitutive and inducible expression of the epithelial antigen MUC1 (CD227) in human T cells. Exp Cell Res 2002; 280:107-18. [PMID: 12372344 DOI: 10.1006/excr.2002.5591] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
MUC1 (CD227) is a large glycoprotein normally produced by epithelial tissue and expressed aberrantly in carcinomas. Here we show that resting human T cells express basal levels of MUC1 mRNA and protein forms with molecular masses of approximately 150 and approximately 250 intracellularly, but lack surface expression. Mitogenic stimulation induces the appearance of new MUC1 mRNA and >300-kDa MUC1 forms. Concomitantly, MUC1 is translocated to the outer cell membrane and its density is continuously modulated according to the cycling status. Inhibitors of mRNA and protein synthesis and of Golgi-dependent protein transport prevent MUC1 induction. Ligation of surface MUC1 has no effect on T-cell proliferation. Also, altering the overall protein structure by preventing glycosylation has no effect. Sizable amounts of >300-kDa glycosylated MUC1 forms are shed by proliferating T cells. This soluble MUC1 does not appear to influence T-cell response, and we found no evidence for MUC1 binding sites on T cells or for transfer of the protein on cell-cell contact. We therefore suggest that MUC1 fulfills the criteria for an early T-cell activation marker but its function remains to be determined. Finally, although we found that cancer- and T cell-associated MUC1 expose common protein core and sialylated epitopes, there is a peptide region, accessible in carcinomas due to an aberrant glycosylation, that is stably not accessible in T cells with potential implications for cancer immunotherapy.
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Affiliation(s)
- Andrea Fattorossi
- Ist. di Ostetricia e Ginecologia, Univ. Cattolica del Sacro Cuore, Rome, Italy.
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Wykes M, MacDonald KPA, Tran M, Quin RJ, Xing PX, Gendler SJ, Hart DNJ, McGuckin MA. MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.4.692] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- M. Wykes
- Dendritic Cell, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia and
| | - K. P. A. MacDonald
- Dendritic Cell, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia and
| | - M. Tran
- Cancer Characterisation Laboratories, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia
| | - R. J. Quin
- Cancer Characterisation Laboratories, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia
| | - P. X. Xing
- Austin Research Institute, Heidelberg, Australia; and
| | | | - D. N. J. Hart
- Dendritic Cell, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia and
| | - M. A. McGuckin
- Cancer Characterisation Laboratories, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, Australia
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Ragupathi G, Livingston P. The case for polyvalent cancer vaccines that induce antibodies. Expert Rev Vaccines 2002; 1:193-206. [PMID: 12901558 DOI: 10.1586/14760584.1.2.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Antibodies are ideally suited for eradicating pathogens from the bloodstream and early tissue invasion. With regard to cancer cells, passively administered and vaccine induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models. A series of cancer cell-surface differentiation antigens have now been identified and synthesized. Antibodies against each can be induced in most vaccinated patients using keyhole limpet hemocyanin conjugate vaccines with a potent immunological adjuvant. Polyvalent vaccines may be required due to tumor cell heterogenely, heterogeneity of the human immune response and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Trials testing the clinical impact of these polyvalent vaccines in the adjuvant setting are planned for the near future.
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Affiliation(s)
- Govind Ragupathi
- Department of Medicine, Sloan-Kettering Cancer Center, New York City, NY 10021, USA
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