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1
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Rus Bakarurraini NAA, Kamarudin AA, Jamal R, Abu N. Engineered T cells for Colorectal Cancer. Immunotherapy 2024; 16:987-998. [PMID: 39229803 PMCID: PMC11485792 DOI: 10.1080/1750743x.2024.2391733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 08/06/2024] [Indexed: 09/05/2024] Open
Abstract
Colorectal cancer (CRC) is a major contributor to global cancer incidence and mortality. Conventional treatments have limitations; hence, innovative approaches are imperative. Recent advancements in cancer research have led to the development of personalized targeted therapies and immunotherapies. Immunotherapy, in particular, T cell-based therapies, exhibited to be promising in enhancing cancer treatment outcomes. This review focuses on the landscape of engineered T cells as a potential option for the treatment of CRC. It highlights the approaches, challenges and current advancements in this field. As the understanding of molecular mechanisms increases, engineered T cells hold great potential in revolutionizing cancer treatment. To fully explore their safety efficacy in improving patient outcomes, further research and clinical trials are necessary.
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Affiliation(s)
| | - Ammar Akram Kamarudin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
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2
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Bowen CM, Sinha KM, Vilar E. Current Trends in Vaccine Development for Hereditary Colorectal Cancer Syndromes. Clin Colon Rectal Surg 2024; 37:146-156. [PMID: 38606044 PMCID: PMC11006444 DOI: 10.1055/s-0043-1770383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
The coming of age for cancer treatment has experienced exponential growth in the last decade with the addition of immunotherapy as the fourth pillar to the fundamentals of cancer treatment-chemotherapy, surgery, and radiation-taking oncology to an astounding new frontier. In this time, rapid developments in computational biology coupled with immunology have led to the exploration of priming the host immune system through vaccination to prevent and treat certain subsets of cancer such as melanoma and hereditary colorectal cancer. By targeting the immune system through tumor-specific antigens-namely, neoantigens (neoAgs)-the future of cancer prevention may lie within arm's reach by employing neoAg vaccines as an immune-preventive modality for hereditary cancer syndromes like Lynch syndrome. In this review, we discuss the history, current trends, utilization, and future direction of neoAg-based vaccines in the setting of hereditary colorectal cancer.
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Affiliation(s)
- Charles M. Bowen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Krishna M. Sinha
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
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3
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Liao K, Yang Q, Xu Y, He Y, Wang J, Li Z, Wu C, Hu J, Wang X. Identification of signature of tumor-infiltrating CD8 T lymphocytes in prognosis and immunotherapy of colon cancer by machine learning. Clin Immunol 2023; 257:109811. [PMID: 37858752 DOI: 10.1016/j.clim.2023.109811] [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: 07/30/2022] [Revised: 09/25/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND To explore the specific marker of CD8+ T cell subsets which are closely related to the prognosis and immunotherapy of patients with colon cancer. METHODS 18 kinds of immune cell expression profile data sets were obtained from GEO database. Compared with other immune cell types, the specific markers of CD8 (+) T cells (TI-CD8) in colorectal cancer were screened. Regression analyses were used to further screen prognostic related genes and construct a prognostic evaluation model. The patients were stratified and analyzed according to the risk scores, KRAS mutation status, stage, lymphatic infiltration and other indicators. The landscape of infiltration level, mutation and copy number variation of immune subsets in high and low TI-CD8Sig score groups were compared and analyzed. The difference of drug response between high and low TI-CD8Sig score groups was analyzed. Differential expression of the model genes was verified by the HPA database. RESULTS Six prognostic-related CD8T cell-specific gene targets were further screened, and the prognostic evaluation model was constructed. The AUC value of the model is >0.75. FAT3 and UNC13C showed a high mutation state in the low-risk group, while USH2A, MUC5B et al. specifically showed a high mutation state in the high-risk group. Compared with the low-risk group, the high-risk group had lower effective rate of drug response. The expression of PD-1 gene was positively correlated with the level of TI-CD8Sig score. CONCLUSION The risk assessment model based on CD8T cell-specific marker genes can effectively predict the prognosis and the drug response of patients with CRC.
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Affiliation(s)
- Kaili Liao
- Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Jiangxi Province Key Laboratory of Laboratory Medicine, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Qijun Yang
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Yuhan Xu
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Yingcheng He
- Queen Mary College of Nanchang University, Xuefu Road, Nanchang, Jiangxi 330001, China
| | - Jingyi Wang
- School of Public Health of Nanchang University, Nanchang, Jiangxi 330001, China
| | - Zimeng Li
- School of Public Health of Nanchang University, Nanchang, Jiangxi 330001, China
| | - Chengfeng Wu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Jialing Hu
- Department of Emergency, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi 330006, China
| | - Xiaozhong Wang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Jiangxi Province Key Laboratory of Laboratory Medicine, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, No. 1 Minde Road, Nanchang, Jiangxi 330006, China.
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4
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Eralp Y, Ates U. Clinical Applications of Combined Immunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review. Vaccines (Basel) 2023; 11:1545. [PMID: 37896948 PMCID: PMC10610904 DOI: 10.3390/vaccines11101545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023] Open
Abstract
Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.
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Affiliation(s)
- Yesim Eralp
- Maslak Acıbadem Hospital, Acıbadem University, Istanbul 34398, Turkey
| | - Utku Ates
- Biotech4life Tissue and Cell R&D Center, Stembio Cell and Tissue Technologies, Inc., Istanbul 34398, Turkey
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5
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Martinis E, Ricci C, Trevisan C, Tomadini G, Tonon S. Cancer Vaccines: From the State of the Art to the Most Promising Frontiers in the Treatment of Colorectal Cancer. Pharmaceutics 2023; 15:1969. [PMID: 37514155 PMCID: PMC10383643 DOI: 10.3390/pharmaceutics15071969] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Colorectal cancer represents 10% of all new cancer cases each year and accounts for almost 10% of all cancer deaths. According to the WHO, by 2040 there will be a 60% increase in colorectal cancer cases. These data highlight the need to explore new therapeutic strategies. Classical interventions include surgical resection, chemotherapy and radiotherapy, which are invasive strategies that have many side effects on the patients and greatly affect their quality of life. A great advance in the treatment of this cancer type, as well as of all the others, could be the development of a vaccination strategy preventing the onset, the progression or the relapse of the pathology. In this review, we summarize the main vaccination strategies that are being studied for the treatment of colorectal cancer (CRC) and finally explore the possibility of using B-cells for the development of a new type of vaccine.
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Affiliation(s)
- Eleonora Martinis
- Department of Medicine, University of Udine, Piazzale Kolbe 4 Udine, 33100 Udine, Italy
| | - Carolina Ricci
- Department of Medicine, University of Udine, Piazzale Kolbe 4 Udine, 33100 Udine, Italy
| | - Caterina Trevisan
- Department of Medicine, University of Udine, Piazzale Kolbe 4 Udine, 33100 Udine, Italy
| | - Gaia Tomadini
- Department of Medicine, University of Udine, Piazzale Kolbe 4 Udine, 33100 Udine, Italy
| | - Silvia Tonon
- Department of Medicine, University of Udine, Piazzale Kolbe 4 Udine, 33100 Udine, Italy
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6
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Yuan J, Li J, Gao C, Jiang C, Xiang Z, Wu J. Immunotherapies catering to the unmet medical need of cold colorectal cancer. Front Immunol 2022; 13:1022190. [PMID: 36275766 PMCID: PMC9579278 DOI: 10.3389/fimmu.2022.1022190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
As a common malignant tumor of gastrointestinal tract, the incidence of colorectal cancer (CRC) has gradually increased in recent years. In western developed countries, it has even become the second largest malignant tumor next to lung cancer. Immunotherapy is a hot topic in the field of cancer therapy, including immune checkpoint blockade (ICB), adoptive cell therapy (ACT), cancer vaccines and cytokines, aiming to improve the ability of the immune system to recognize, target and eliminate cancer cells. However, cold CRC, which accounts for a high proportion of CRC, is not so reactive to it. The development of immunotherapy to prevent cancer cells from forming "immune escape" pathways to the immune system in cold CRC, has been under increasing study attention. There is proof that an organic combination of radiotherapy, chemotherapy, and several immunotherapies can considerably boost the immune system's capacity to eradicate tumor cells. In this review, we summarized the role of immunotherapy in colorectal cancer. In addition, we propose a breakthrough and strategy to improve the role of immunotherapy in cold CRC based on its characteristics.
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Affiliation(s)
- Jun Yuan
- Department of Clinical Laboratory, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, China
| | - Jiarui Li
- Zhejiang University School of Medicine, Hangzhou, China
| | - Ce Gao
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Chun Jiang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Wu
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
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7
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Eisemann T, Wechsler-Reya RJ. Coming in from the cold: overcoming the hostile immune microenvironment of medulloblastoma. Genes Dev 2022; 36:514-532. [PMID: 35680424 PMCID: PMC9186392 DOI: 10.1101/gad.349538.122] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families.
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Affiliation(s)
- Tanja Eisemann
- Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA
| | - Robert J Wechsler-Reya
- Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.,Department of Pediatrics, University of California at San Diego, La Jolla, California 92161, USA
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8
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Hossain MS, Karuniawati H, Jairoun AA, Urbi Z, Ooi DJ, John A, Lim YC, Kibria KMK, Mohiuddin AM, Ming LC, Goh KW, Hadi MA. Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers (Basel) 2022; 14:1732. [PMID: 35406504 PMCID: PMC8996939 DOI: 10.3390/cancers14071732] [Citation(s) in RCA: 320] [Impact Index Per Article: 106.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/22/2022] [Accepted: 03/27/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the second most deadly cancer. Global incidence and mortality are likely to be increased in the coming decades. Although the deaths associated with CRC are very high in high-income countries, the incidence and fatalities related to CRC are growing in developing countries too. CRC detected early is entirely curable by surgery and subsequent medications. However, the recurrence rate is high, and cancer drug resistance increases the treatment failure rate. Access to early diagnosis and treatment of CRC for survival is somewhat possible in developed countries. However, these facilities are rarely available in developing countries. Highlighting the current status of CRC, its development, risk factors, and management is crucial in creating public awareness. Therefore, in this review, we have comprehensively discussed the current global epidemiology, drug resistance, challenges, risk factors, and preventive and treatment strategies of CRC. Additionally, there is a brief discussion on the CRC development pathways and recommendations for preventing and treating CRC.
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Affiliation(s)
- Md. Sanower Hossain
- Department of Biomedical Science, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, Kuantan 25200, Pahang, Malaysia
- Faculty of Science, Sristy College of Tangail, Tangail 1900, Bangladesh
| | - Hidayah Karuniawati
- Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia; (H.K.); (A.A.J.)
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Muhammadiyah Surakarta, Surakarta 57102, Indonesia
| | - Ammar Abdulrahman Jairoun
- Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia; (H.K.); (A.A.J.)
- Health and Safety Department, Dubai Municipality, Dubai 67, United Arab Emirates
| | - Zannat Urbi
- Department of Industrial Biotechnology, Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Kuantan 26300, Pahang, Malaysia;
| | - Der Jiun Ooi
- Department of Oral Biology & Biomedical Sciences, Faculty of Dentistry, MAHSA University, Jenjarom 42610, Selangor, Malaysia;
| | - Akbar John
- Institute of Oceanography and Maritime Studies (INOCEM), Kulliyyah of Science, International Islamic University Malaysia, Kuantan 25200, Pahang, Malaysia;
| | - Ya Chee Lim
- PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei;
| | - K. M. Kaderi Kibria
- Department of Biotechnology & Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh; (K.M.K.K.); (A.K.M.M.)
| | - A.K. M. Mohiuddin
- Department of Biotechnology & Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh; (K.M.K.K.); (A.K.M.M.)
| | - Long Chiau Ming
- PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei;
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Negeri Sembilan, Malaysia;
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9
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Subtil B, Cambi A, Tauriello DVF, de Vries IJM. The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer. Front Immunol 2021; 12:724883. [PMID: 34691029 PMCID: PMC8527179 DOI: 10.3389/fimmu.2021.724883] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
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Affiliation(s)
- Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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10
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Azadi A, Golchini A, Delazar S, Abarghooi Kahaki F, Dehnavi SM, Payandeh Z, Eyvazi S. Recent Advances on Immune Targeted Therapy of Colorectal Cancer Using bi-Specific Antibodies and Therapeutic Vaccines. Biol Proced Online 2021; 23:13. [PMID: 34193050 PMCID: PMC8245152 DOI: 10.1186/s12575-021-00147-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/12/2021] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is a universal heterogeneous disease that is characterized by genetic and epigenetic alterations. Immunotherapy using monoclonal antibodies (mAb) and cancer vaccines are substitute strategies for CRC treatment. When cancer immunotherapy is combined with chemotherapy, surgery, and radiotherapy, the CRC treatment would become excessively efficient. One of the compelling immunotherapy approaches to increase the efficiency of CRC therapy is the deployment of therapeutic mAbs, nanobodies, bi-specific antibodies and cancer vaccines, which improve clinical outcomes in patients. Also, among the possible therapeutic approaches for CRC patients, gene vaccines in combination with antibodies are recently introduced as a new perspective. Here, we aimed to present the current progress in CRC immunotherapy, especially using Bi-specific antibodies and dendritic cells mRNA vaccines. For this aim, all data were extracted from Google Scholar, PubMed, Scopus, and Elsevier, using keywords cancer vaccines; CRC immunotherapy and CRC mRNA vaccines. About 97 articles were selected and investigated completely based on the latest developments and novelties on bi-specific antibodies, mRNA vaccines, nanobodies, and MGD007.
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Affiliation(s)
- Ali Azadi
- Department of Medicine, De La Salle Health Sciences Institute, Dasmariñas, Philippines
| | - Alireza Golchini
- Cancer surgery Department; Shiraz Medical School, Shiraz University of medical Sciences, Shiraz, Iran
| | - Sina Delazar
- Department of Radiology, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Abarghooi Kahaki
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Dehnavi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Payandeh
- Immunology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Eyvazi
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
- Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran
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11
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Vaccines in Gastrointestinal Malignancies: From Prevention to Treatment. Vaccines (Basel) 2021; 9:vaccines9060647. [PMID: 34199248 PMCID: PMC8231997 DOI: 10.3390/vaccines9060647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) malignancies are some of the most common and devastating malignancies and include colorectal, gastric, esophageal, hepatocellular, and pancreatic carcinomas, among others. Five-year survival rates for many of these malignancies remain low. The majority presents at an advanced stage with limited treatment options and poor overall survival. Treatment is advancing but not at the same speed as other malignancies. Chemotherapy and radiation treatments are still only partially effective in GI malignancies and cause significant side effects. Thus, there is an urgent need for novel strategies in the treatment of GI malignancies. Recently, immunotherapy and checkpoint inhibitors have entered as potential new therapeutic options for patients, and thus, cancer vaccines may play a major role in the future of treatment for these malignancies. Further advances in understanding the interaction between the tumor and immune system have led to the development of novel agents, such as cancer vaccines.
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12
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Keshavarz-Fathi M, Rezaei N. Cancer Immunoprevention: Current Status and Future Directions. Arch Immunol Ther Exp (Warsz) 2021; 69:3. [PMID: 33638703 DOI: 10.1007/s00005-021-00604-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 02/06/2021] [Indexed: 12/24/2022]
Abstract
Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunoprevention has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunoprevention that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immunomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention.
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Affiliation(s)
- Mahsa Keshavarz-Fathi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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13
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Stevens D, Ingels J, Van Lint S, Vandekerckhove B, Vermaelen K. Dendritic Cell-Based Immunotherapy in Lung Cancer. Front Immunol 2021; 11:620374. [PMID: 33679709 PMCID: PMC7928408 DOI: 10.3389/fimmu.2020.620374] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer remains the leading cause of cancer-related death worldwide. The advent of immune checkpoint inhibitors has led to a paradigm shift in the treatment of metastatic non-small cell and small cell lung cancer. However, despite prolonged overall survival, only a minority of the patients derive clinical benefit from these treatments suggesting that the full anti-tumoral potential of the immune system is not being harnessed yet. One way to overcome this problem is to combine immune checkpoint blockade with different strategies aimed at inducing or restoring cellular immunity in a tumor-specific, robust, and durable way. Owing to their unique capacity to initiate and regulate T cell responses, dendritic cells have been extensively explored as tools for immunotherapy in many tumors, including lung cancer. In this review, we provide an update on the nearly twenty years of experience with dendritic cell-based immunotherapy in lung cancer. We summarize the main results from the early phase trials and give an overview of the future perspectives within this field.
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Affiliation(s)
- Dieter Stevens
- Respiratory Medicine - Thoracic Oncology Cluster, Ghent University Hospital, Ghent, Belgium.,Respiratory Medicine - Tumor Immunology Laboratory, Ghent University, Ghent, Belgium
| | - Joline Ingels
- Department of Diagnostic Sciences, Ghent University Hospital, Ghent, Belgium
| | - Sandra Van Lint
- Respiratory Medicine - Tumor Immunology Laboratory, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Bart Vandekerckhove
- Department of Diagnostic Sciences, Ghent University Hospital, Ghent, Belgium.,GMP Cell Therapy Unit, Department of Regenerative Medicine, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Karim Vermaelen
- Respiratory Medicine - Thoracic Oncology Cluster, Ghent University Hospital, Ghent, Belgium.,Respiratory Medicine - Tumor Immunology Laboratory, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
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14
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Ng CX, Lee SH. The Potential Use of Anticancer Peptides (ACPs) in the Treatment of Hepatocellular Carcinoma. Curr Cancer Drug Targets 2020; 20:187-196. [PMID: 31713495 DOI: 10.2174/1568009619666191111141032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/22/2019] [Accepted: 09/23/2019] [Indexed: 01/19/2023]
Abstract
Peptides have acquired increasing interest as promising therapeutics, particularly as anticancer alternatives during recent years. They have been reported to demonstrate incredible anticancer potentials due to their low manufacturing cost, ease of synthesis and great specificity and selectivity. Hepatocellular carcinoma (HCC) is among the leading cause of cancer death globally, and the effectiveness of current liver treatment has turned out to be a critical issue in treating the disease efficiently. Hence, new interventions are being explored for the treatment of hepatocellular carcinoma. Anticancer peptides (ACPs) were first identified as part of the innate immune system of living organisms, demonstrating promising activity against infectious diseases. Differentiated beyond the traditional effort on endogenous human peptides, the discovery of peptide drugs has evolved to rely more on isolation from other natural sources or through the medicinal chemistry approach. Up to the present time, the pharmaceutical industry intends to conduct more clinical trials for the development of peptides as alternative therapy since peptides possess numerous advantages such as high selectivity and efficacy against cancers over normal tissues, as well as a broad spectrum of anticancer activity. In this review, we present an overview of the literature concerning peptide's physicochemical properties and describe the contemporary status of several anticancer peptides currently engaged in clinical trials for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Chu Xin Ng
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
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15
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Kan S, Bito T, Shimabuku M, Taguchi J, Ohkusa T, Shimodaira S, Sugiyama H, Koido S. Impact of mature dendritic cells pulsed with a novel WT1 helper peptide on the induction of HLA‑A2‑restricted WT1‑reactive CD8+ T cells. Int J Oncol 2020; 57:1047-1056. [PMID: 32945369 DOI: 10.3892/ijo.2020.5110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 07/31/2020] [Indexed: 11/06/2022] Open
Abstract
The proliferation and activation of CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lymphocytes (CTLs) that produce interferon‑γ (IFN‑γ) is an essential action of effective cancer vaccines. Recently, a novel Wilms' tumor 1 (WT1) helper peptide (WT1 HP34‑51; amino acid sequence, WAPVLDFAPPGASAYGSL) applicable for various human leukocyte antigen (HLA) subtypes (HLA‑DR, HLA‑DP and HLA‑DQ) was reported to increase peptide immunogenicity; however, the function of WT1 HP34‑51 remains unclear. In the present study, mature dendritic cells (mDCs) pulsed with WT1 HP34‑51 (mDC/WT1 HP34‑51) activated not only WT1‑specific CD4+ T cells but also CD8+ T cells that produced IFN‑γ following stimulation with immature dendritic cells (imDCs) pulsed with WT1 killer peptide (imDC/WT1 KP37‑45) in an HLA‑A*02:01‑ or HLA‑A*02:06‑restricted manner. Furthermore, the activated WT1‑reactive CD4+ Th1 cells were predominantly effector memory (EM) T cells. In 5 of 12 (41.7%) patients with cancer carrying the HLA‑A*02:01 or HLA‑A*02:06 allele, WT1‑reactive CD8+ T cells stimulated with mDC/WT1 HP34‑51 enhanced their levels of WT1 KP37‑45‑specific IFN‑γ production, with an increase >10%. Simultaneous activation of CD4+ and CD8+ T cells occurred more often when stimulation with mDC/WT1 HP34‑51 was combined with imDC/WT1 KP37‑45 restimulation. These results indicated that the novel mDC/WT1 HP34‑51 combination induced responses by WT1‑specific EM CD4+ Th1 cells and HLA‑A*02:01‑ or HLA‑A*02:06‑restricted CD8+ CTLs, suggesting its potential as a WT1‑targeting cancer vaccine.
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Affiliation(s)
- Shin Kan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Tsuuse Bito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Masamori Shimabuku
- Tokyo Midtown Center for Advanced Medical Science and Technology, Tokyo 107‑6206, Japan
| | - Junichi Taguchi
- Tokyo Midtown Center for Advanced Medical Science and Technology, Tokyo 107‑6206, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Shigetaka Shimodaira
- Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa 920‑0293, Japan
| | - Haruo Sugiyama
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565‑0871, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
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16
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Xu S, Yang K, Li R, Zhang L. mRNA Vaccine Era-Mechanisms, Drug Platform and Clinical Prospection. Int J Mol Sci 2020; 21:E6582. [PMID: 32916818 PMCID: PMC7554980 DOI: 10.3390/ijms21186582] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/26/2020] [Accepted: 08/30/2020] [Indexed: 12/14/2022] Open
Abstract
Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis. At the same time, some suggestions for future mRNA vaccine development about storage methods, safety concerns, and personalized vaccine synthesis can be found in the context.
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Affiliation(s)
- Shuqin Xu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; (S.X.); (K.Y.)
| | - Kunpeng Yang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; (S.X.); (K.Y.)
| | - Rose Li
- M.B.B.S., School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;
| | - Lu Zhang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; (S.X.); (K.Y.)
- Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China
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17
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Picard E, Verschoor CP, Ma GW, Pawelec G. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer. Front Immunol 2020; 11:369. [PMID: 32210966 PMCID: PMC7068608 DOI: 10.3389/fimmu.2020.00369] [Citation(s) in RCA: 332] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
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Affiliation(s)
- Emilie Picard
- Health Sciences North Research Institute, Sudbury, ON, Canada
| | | | - Grace W Ma
- Department of Surgery, Health Sciences North, Sudbury, ON, Canada
| | - Graham Pawelec
- Health Sciences North Research Institute, Sudbury, ON, Canada.,Department of Immunology, University of Tübingen, Tübingen, Germany
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18
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Belderbos RA, Aerts JGJV, Vroman H. Enhancing Dendritic Cell Therapy in Solid Tumors with Immunomodulating Conventional Treatment. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:67-81. [PMID: 31020037 PMCID: PMC6475716 DOI: 10.1016/j.omto.2019.03.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key initiator of tumor-specific immune responses. These characteristics are exploited by DC therapy, where DCs are ex vivo loaded with tumor-associated antigens (TAAs) and used to induce tumor-specific immune responses. Unfortunately, clinical responses remain limited to a proportion of the patients. Tumor characteristics and the immunosuppressive tumor microenvironment (TME) of the tumor are likely hampering efficacy of DC therapy. Therefore, reducing the immunosuppressive TME by combining DC therapy with other treatments could be a promising strategy. Initially, conventional cancer therapies, such as chemotherapy and radiotherapy, were thought to specifically target cancerous cells. Recent insights indicate that these therapies additionally augment tumor immunity by targeting immunosuppressive cell subsets in the TME, inducing immunogenic cell death (ICD), or blocking inhibitory molecules. Therefore, combining DC therapy with registered therapies such as chemotherapy, radiotherapy, or checkpoint inhibitors could be a promising treatment strategy to improve the efficacy of DC therapy. In this review, we evaluate various clinical applicable combination strategies to improve the efficacy of DC therapy.
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Affiliation(s)
- Robert A Belderbos
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
| | - Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
| | - Heleen Vroman
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
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19
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Wagner S, Mullins CS, Linnebacher M. Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens. World J Gastroenterol 2018; 24:5418-5432. [PMID: 30622371 PMCID: PMC6319136 DOI: 10.3748/wjg.v24.i48.5418] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 12/11/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023] Open
Abstract
Therapeutic options for the treatment of colorectal cancer (CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hyper-mutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens (TAAs) and tumor-specific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptide-based vaccines achievable by adjuvants and immune-stimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens - in CRC almost exclusively neoantigens - which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immune-stimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.
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Affiliation(s)
- Sandra Wagner
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
| | - Christina S Mullins
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
| | - Michael Linnebacher
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
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20
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van Ee TJ, Van Acker HH, van Oorschot TG, Van Tendeloo VF, Smits EL, Bakdash G, Schreibelt G, de Vries IJM. BDCA1+CD14+ Immunosuppressive Cells in Cancer, a Potential Target? Vaccines (Basel) 2018; 6:E65. [PMID: 30235890 PMCID: PMC6161086 DOI: 10.3390/vaccines6030065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/17/2018] [Accepted: 09/18/2018] [Indexed: 12/22/2022] Open
Abstract
Dendritic cell (DC) vaccines show promising effects in cancer immunotherapy. However, their efficacy is affected by a number of factors, including (1) the quality of the DC vaccine and (2) tumor immune evasion. The recently characterized BDCA1+CD14+ immunosuppressive cells combine both aspects; their presence in DC vaccines may directly hamper vaccine efficacy, whereas, in patients, BDCA1+CD14+ cells may suppress the induced immune response in an antigen-specific manner systemically and at the tumor site. We hypothesize that BDCA1+CD14+ cells are present in a broad spectrum of cancers and demand further investigation to reveal treatment opportunities and/or improvement for DC vaccines. In this review, we summarize the findings on BDCA1+CD14+ cells in solid cancers. In addition, we evaluate the presence of BDCA1+CD14+ cells in leukemic cancers. Preliminary results suggest that the presence of BDCA1+CD14+ cells correlates with clinical features of acute and chronic myeloid leukemia. Future research focusing on the differentiation from monocytes towards BDCA1+CD14+ cells could reveal more about their cell biology and clinical significance. Targeting these cells in cancer patients may improve the outcome of cancer immunotherapy.
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Affiliation(s)
- Thomas J van Ee
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen 6525 GA, The Netherlands.
| | - Heleen H Van Acker
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp 2000, Belgium.
| | - Tom G van Oorschot
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen 6525 GA, The Netherlands.
| | - Viggo F Van Tendeloo
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp 2000, Belgium.
| | - Evelien L Smits
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp 2000, Belgium.
- Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium.
| | - Ghaith Bakdash
- Allergic Inflammation Discovery Performance Unit, Respiratory Therapy Area, GlaxoSmithKline, Stevenage SG1 2NY, UK.
| | - Gerty Schreibelt
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen 6525 GA, The Netherlands.
| | - I Jolanda M de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen 6525 GA, The Netherlands.
- Department of Medical Oncology; Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen 6525 GA, The Netherlands.
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21
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Galun D, Bogdanovic A, Djokic Kovac J, Bulajic P, Loncar Z, Zuvela M. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative-intent surgery for hepatocellular carcinoma: experience from a developing country. Cancer Manag Res 2018; 10:977-988. [PMID: 29765248 PMCID: PMC5942394 DOI: 10.2147/cmar.s161398] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose The aim of the study was to evaluate a prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on long-term survival of cirrhotic and noncirrhotic hepatocellular cancer (HCC) patients managed by a curative-intent liver surgery in a developing country. Patients and methods During the study period between November 1, 2001, and December 31, 2012, 109 patients underwent potentially curative hepatectomy for HCC. Data were retrospectively reviewed from the prospectively collected database. The median follow-up was 25 months. NLR was estimated by dividing an absolute neutrophil count by an absolute lymphocyte count from the differential blood count. Receiver operating characteristic curve was constructed to assess the ability of NLR to predict long-term outcomes and to determine an optimal cutoff value for all patients group, the subgroup with cirrhosis, and the subgroup without cirrhosis. The optimal cutoff values were 1.28, 1.28, and 2.09, respectively. Results The overall 3- and 5-year survival rates were 49% and 45%, respectively, for low NLR group and 38% and 26%, respectively, for high NLR group. The difference was statistically significant (p=0.015). Overall survival was similar between low and high NLR groups in patients with cirrhosis; no difference was found between the groups (p=0.124). In patients without cirrhosis, low NLR group had longer overall survival compared with high NLR group (p=0.015). Univariate analysis identified four factors as significant predictors of long-term survival: cirrhosis, Child-Pugh score, platelet count, and NLR. On multivariate analysis, only platelet count and NLR were independent prognostic factors of long-term survival. Conclusion Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative-intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed.
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Affiliation(s)
- Danijel Galun
- HPB Unit, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
| | | | - Jelena Djokic Kovac
- Medical School, University of Belgrade, Belgrade, Serbia.,Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Belgrade, Serbia
| | - Predrag Bulajic
- HPB Unit, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia
| | - Zlatibor Loncar
- Medical School, University of Belgrade, Belgrade, Serbia.,Emergency Center, Clinical Center of Serbia, Belgrade, Serbia
| | - Marinko Zuvela
- HPB Unit, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
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22
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Mennens SFB, Bolomini-Vittori M, Weiden J, Joosten B, Cambi A, van den Dries K. Substrate stiffness influences phenotype and function of human antigen-presenting dendritic cells. Sci Rep 2017; 7:17511. [PMID: 29235514 PMCID: PMC5727489 DOI: 10.1038/s41598-017-17787-z] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/30/2017] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) are specialized immune cells that scan peripheral tissues for foreign material or aberrant cells and, upon recognition of such danger signals, travel to lymph nodes to activate T cells and evoke an immune response. For this, DCs travel large distances through the body, encountering a variety of microenvironments with different mechanical properties such as tissue stiffness. While immune-related pathological conditions such as fibrosis or cancer are associated with tissue stiffening, the role of tissue stiffness in regulating key functions of DCs has not been studied yet. Here, we investigated the effect of substrate stiffness on the phenotype and function of DCs by conditioning DCs on polyacrylamide substrates of 2, 12 and 50 kPa. Interestingly, we found that C-type lectin expression on immature DCs (iDCs) is regulated by substrate stiffness, resulting in differential antigen internalization. Furthermore, we show that substrate stiffness affects β2 integrin expression and podosome formation by iDCs. Finally, we demonstrate that substrate stiffness influences CD83 and CCR7 expression on mature DCs, the latter leading to altered chemokine-directed migration. Together, our results indicate that DC phenotype and function are affected by substrate stiffness, suggesting that tissue stiffness is an important determinant for modulating immune responses.
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Affiliation(s)
- Svenja F B Mennens
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Matteo Bolomini-Vittori
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Jorieke Weiden
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Ben Joosten
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands.
| | - Koen van den Dries
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, The Netherlands.
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23
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Saleh K, Khalife-Saleh N, Kourie HR, Chahine G. How and when adjuvant treatment should be intensified in stage III colorectal cancers? Future Oncol 2017; 13:1999-2006. [PMID: 28829195 DOI: 10.2217/fon-2017-0197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The adjuvant chemotherapy (FOLFOX) represents the standard of care in stage III colon cancer with some exceptions in old patients. Adjuvant treatment must also be discussed in high-risk stage II colon cancer. However, 40-50% of patients develop disease recurrence after curative R0 surgical resection. The liver was the most common site of recurrence followed by peritoneum. Although adjuvant chemotherapy improved disease-free survival and overall survival, 5-year overall survival remains less than 55% in stage III colon cancer. Different strategies could be adopted to escalate the standard adjuvant chemotherapy in these patients going from aggressive intravenous chemotherapy, hepatic arterial infusion chemotherapy, hyperthermic intraperitoneal chemotherapy to adding targeted therapies or immunotherapies. We reported in this review the published and ongoing trials evaluating these treatment modalities in colon cancer.
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Affiliation(s)
- Khalil Saleh
- Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Nadine Khalife-Saleh
- Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | | | - Georges Chahine
- Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
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24
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The Roles of Carcinoembryonic Antigen in Liver Metastasis and Therapeutic Approaches. Gastroenterol Res Pract 2017; 2017:7521987. [PMID: 28588612 PMCID: PMC5447280 DOI: 10.1155/2017/7521987] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 04/16/2017] [Indexed: 12/22/2022] Open
Abstract
Metastasis is a highly complicated and sequential process in which primary cancer spreads to secondary organic sites. Liver is a well-known metastatic organ from colorectal cancer. Carcinoembryonic antigen (CEA) is expressed in most gastrointestinal, breast, and lung cancer cells. Overexpression of CEA is closely associated with liver metastasis, which is the main cause of death from colorectal cancer. CEA is widely used as a diagnostic and prognostic tumor marker in cancer patients. It affects many steps of liver metastasis from colorectal cancer cells. CEA inhibits circulating cancer cell death. CEA also binds to heterogeneous nuclear RNA binding protein M4 (hnRNP M4), a Kupffer cell receptor protein, and activates Kupffer cells to secrete various cytokines that change the microenvironments for the survival of colorectal cancer cells in the liver. CEA also activates cell adhesion-related molecules. The close correlation between CEA and cancer has spurred the exploration of many CEA-targeted approaches as anticancer therapeutics. Understanding the detailed functions and mechanisms of CEA in liver metastasis will provide great opportunities for the improvement of anticancer approaches against colorectal cancers. In this report, the roles of CEA in liver metastasis and CEA-targeting anticancer modalities are reviewed.
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25
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Khoury HJ, Collins RH, Blum W, Stiff PS, Elias L, Lebkowski JS, Reddy A, Nishimoto KP, Sen D, Wirth ED, Case CC, DiPersio JF. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia. Cancer 2017; 123:3061-3072. [PMID: 28411378 DOI: 10.1002/cncr.30696] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 02/21/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML. METHODS hTERT-DCs were produced from patient-specific leukapheresis, electroporated with an mRNA-encoding hTERT and a lysosomal-targeting sequence, and cryopreserved. A total of 22 patients with a median age of 58 years (range, 30-75 years) with intermediate-risk or high-risk AML in first or second complete remission (CR) were enrolled. hTERT-DCs were generated for 24 patients (73%). A median of 17 intradermal vaccinations (range, 6-32 intradermal vaccinations) containing 1×107 cells were administered as 6 weekly injections followed by 6 biweekly injections. A total of 21 patients (16 in first CR, 3 in second CR, and 2 with early disease recurrence) received hTERT-DCs. RESULTS hTERT-DCs were well tolerated with no severe toxicities reported, with the exception of 1 patient who developed idiopathic thrombocytopenic purpura. Of the 19 patients receiving hTERT-DCs in CR, 11 patients (58%) developed hTERT-specific T-cell responses that primarily were targeted toward hTERT peptides with predicted low human leukocyte antigen (HLA)-binding affinities. With a median follow-up of 52 months, 58% of patients in CR (11 of 19 patients) were free of disease recurrence at the time of their last follow-up visit; 57% of the patients who were aged ≥60 years (4 of 7 patients) also were found to be free of disease recurrence at a median follow-up of 54 months. CONCLUSIONS The generation of hTERT-DCs is feasible and vaccination with hTERT-DCs appears to be safe and may be associated with favorable recurrence-free survival. Cancer 2017;123:3061-72. © 2017 American Cancer Society.
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Affiliation(s)
- Hanna J Khoury
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia
| | - Robert H Collins
- Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
| | - William Blum
- Department of Hematology, The Ohio State University, Columbus, Ohio
| | - Patrick S Stiff
- Department of Medicine, Loyola University, Maywood, Illinois
| | | | | | | | | | - Debasish Sen
- Asterias Biotherapeutics Inc, Menlo Park, California
| | | | - Casey C Case
- Asterias Biotherapeutics Inc, Menlo Park, California
| | - John F DiPersio
- Department of Oncology, Washington University School of Medicine, St. Louis, Missouri
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Teramoto K, Ozaki Y, Hanaoka J, Sawai S, Tezuka N, Fujino S, Daigo Y, Kontani K. Predictive biomarkers and effectiveness of MUC1-targeted dendritic-cell-based vaccine in patients with refractory non-small cell lung cancer. Ther Adv Med Oncol 2017; 9:147-157. [PMID: 28344660 PMCID: PMC5349424 DOI: 10.1177/1758834016678375] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The dendritic cell (DC)-based vaccine targeting the highly immunogenic tumor antigen, MUC1, has been promising for a cancer immunotherapy; however, predictive biomarkers for beneficial clinical responses of the vaccine remain to be determined. METHODS DCs loaded with MUC1-derived peptide were subcutaneously administered to patients with MUC1-positive non-small cell lung cancer (NSCLC) that was refractory to standard anticancer therapies, every 2 weeks. The effectiveness and tolerability of the vaccine were evaluated, and predictive biomarkers of clinical responses were explored. RESULTS Between August 2005 and May 2015, 40 patients received the vaccines. The median survival time (MST) after the initial vaccination was 7.4 months, and the 1-year survival rate was 25.0%. The MST for patients who received more than six vaccinations was 9.5 months, and the 1-year survival rate was 39.3%. In this cohort, patients who experienced immune-related adverse events, including skin reactions at the vaccination site and fever, had significantly longer survival times compared with patients without those immune-related adverse events (12.6 versus 6.7 months, p = 0.042). Longer survival times were also observed in patients whose peripheral white blood cells contained >20.0% lymphocytes (12.6 versus 4.5 months; p = 0.014). MUC1-specific cytotoxic immune responses were achieved in all of seven patients analyzed who received six vaccinations. CONCLUSION The MUC1-targeted DC-based vaccine induced an antitumor immune response that promoted prolonged survival of patients with refractory NSCLC. The occurrence of immune-related adverse events and having a higher percentage of peripheral lymphocytes were predictive biomarkers of a beneficial clinical response during cancer immunotherapy for NSCLC.
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Affiliation(s)
- Koji Teramoto
- Department of Medical Oncology and Surgery, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Yoshitomo Ozaki
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Jun Hanaoka
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Satoru Sawai
- Departments of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Noriaki Tezuka
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Shozo Fujino
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yataro Daigo
- Department of Medical Oncology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Keiichi Kontani
- Department of Respiratory, Breast and Endocrine Surgery, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
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Radej S, Roliński J, Rawicz-Pruszyński K, Bury P, Borowski G, Furmaga J, Chrościcki A, Wallner G, Maciejewski R. Immunomodelling Characteristics of Mature Dendritic Cells Stimulated by Colon Cancer Cells Lysates. POLISH JOURNAL OF SURGERY 2017; 87:71-82. [PMID: 26146098 DOI: 10.1515/pjs-2015-0022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Indexed: 11/15/2022]
Abstract
UNLABELLED Application of cells with high TAA (tumor associated antigen) presentation potential seems to be crucial in neoplasia immunotherapy. Such feature is distributed in dendritic cells, which present peptides from processed TAA - MHC molecules complex to the T cells of a host. The aim of the study was to assess the influence of colon neoplasia tissue lysate on functioning of generated autologous DC's in the field of autologous CD4+ lymphocytes immunological response towards Th1/Th2 under in vitro environment together with comparison and assessment of DCs' immunosuppressive properties acquired from patients with colon cancer. MATERIAL AND METHODS The population of this study consisted of 16 healthy- controls, 36colon cancer patients. Blood samples were collected 24h before planned surgery and preventive antibiotic therapy. Neoplastic tissue sample, was digested for cell lysates preparation. DC's generation from PBMC was carried out in standard conditionsand medium enriched with rhGM-CSF and rhIL-4. Mature DC`s and cocultured autologous CD4 lymphocytes immunophenotype assessment was analyzed with flow cytometer. Intracellular and culture medium cytokines concentration was analyzed with ELISA and FACS method. RESULTS DC`s generated from colon cancer patients stimulated with lysates presented greater maturity, lower expression of CD206 antigen, significantly higher expression of HLA-DR, CD208 and CD209 and high intracellular expression of IL-12, compared to non-stimulated cells. CONCLUSIONS The neoplastic tissue in vivo produces a number of substances having an unfavorable effect on immune system, our results suggests using lysates as good dendritic cells stimulators that possibly could have application in colon cancer immunotherapy.
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Caputo D, Caricato M, Coppola A, La Vaccara V, Fiore M, Coppola R. Neutrophil to Lymphocyte Ratio (NLR) and Derived Neutrophil to Lymphocyte Ratio (d-NLR) Predict Non-Responders and Postoperative Complications in Patients Undergoing Radical Surgery After Neo-Adjuvant Radio-Chemotherapy for Rectal Adenocarcinoma. Cancer Invest 2016; 34:440-451. [PMID: 27740855 DOI: 10.1080/07357907.2016.1229332] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In order to evaluate neutrophil-to-lymphocyte ratio (NLR) and derived neutrophil-to-lymphocyte ratio (d-NLR) in predicting response and complications in rectal cancer patients who underwent surgery after neo-adjuvant radio-chemotherapy, 87 patients were evaluated. Cutoffs before and after radio-chemotherapy were respectively 2.8 and 3.8 for NLR, and 1.4 and 2.3 for d-NLR. They were analyzed in relation to clinical and pathological outcomes. Patients with preoperative NLR and d-NLR higher than cutoffs had significantly higher rates of tumor regression grade response (TRG ≥ 4) and postoperative complications. Elevated NLR and d-NLR after radio-chemotherapy are associated with worse pathological and clinical outcome.
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Affiliation(s)
- Damiano Caputo
- a Department of General Surgery , University Campus Bio-Medico di Roma , Rome , Italy
| | - Marco Caricato
- a Department of General Surgery , University Campus Bio-Medico di Roma , Rome , Italy
| | - Alessandro Coppola
- b International PhD Programme in Endocrinology and Metabolic Diseases, University Campus Bio-Medico di Roma , Rome , Italy
| | - Vincenzo La Vaccara
- a Department of General Surgery , University Campus Bio-Medico di Roma , Rome , Italy
| | - Michele Fiore
- c Department of Radiation Oncology , University Campus Bio-Medico di Roma , Rome , Italy
| | - Roberto Coppola
- a Department of General Surgery , University Campus Bio-Medico di Roma , Rome , Italy
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Lynch D, Murphy A. The emerging role of immunotherapy in colorectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:305. [PMID: 27668225 DOI: 10.21037/atm.2016.08.29] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Modulation of the interaction between the immune system and the tumor microenvironment has long been a target of cancer research, including colorectal cancer (CRC). Approaches explored to date include vaccines (autologous, peptide, dendritic cell, viral and bacterial), cytokine therapy, toll-like receptors (TLRs), autologous cell therapy and checkpoint inhibition. Until recently these approaches have been shown to have only modest efficacy in reducing tumor burden. However, significant breakthroughs have been made, with the use of checkpoint inhibitors targeting programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4). Immunotherapy now represents a possible avenue of curative treatment for those with chemo-otherwise refractory tumors. Success with this approach to immunotherapy has largely been confined to tumors with high mutational burdens such as melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer. This observation led to the exploration and successful use of checkpoint inhibitors in those with mismatch repair colorectal cancer which have a relatively high mutational burden. Ongoing trials are focused on further exploring the use of checkpoint inhibitors in addition to investigating the various combinations of immunotherapeutic drugs.
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Affiliation(s)
- David Lynch
- Department of Internal Medicine, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA
| | - Adrian Murphy
- Department Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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Kajihara M, Takakura K, Kanai T, Ito Z, Saito K, Takami S, Shimodaira S, Okamoto M, Ohkusa T, Koido S. Dendritic cell-based cancer immunotherapy for colorectal cancer. World J Gastroenterol 2016; 22:4275-86. [PMID: 27158196 PMCID: PMC4853685 DOI: 10.3748/wjg.v22.i17.4275] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/15/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.
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31
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Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother 2016; 65:1249-59. [PMID: 27060000 PMCID: PMC5035655 DOI: 10.1007/s00262-016-1832-7] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 03/23/2016] [Indexed: 12/22/2022]
Abstract
Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC.
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Dendritic Cell-Based Adjuvant Vaccination Targeting Wilms' Tumor 1 in Patients with Advanced Colorectal Cancer. Vaccines (Basel) 2015; 3:1004-18. [PMID: 26690485 PMCID: PMC4693229 DOI: 10.3390/vaccines3041004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 11/19/2015] [Accepted: 12/07/2015] [Indexed: 12/14/2022] Open
Abstract
Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.
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Bhargava A, Bunkar N, Khare NK, Mishra D, Mishra PK. Nanoengineered strategies to optimize dendritic cells for gastrointestinal tumor immunotherapy: from biology to translational medicine. Nanomedicine (Lond) 2015; 9:2187-202. [PMID: 25405796 DOI: 10.2217/nnm.14.115] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-based immunotherapy against GI tract malignancies. Dendritic cell-based vaccines have proven their effectiveness against different established GI tract tumors, yet their success is mainly hindered by the strong tumor-induced suppressive microenvironment. The sustained and targeted release of tumor antigens to dendritic cells using different nanoengineered approaches would be an efficient strategy to overcome established immune tolerance. Encapsulation would result in low diffusivity, restricted movement, effective crosspresentation and enhanced T-cell responses. These nanotherapy-based approaches will certainly help with the designing of clinically translatable dendritic cell-based therapeutic vaccines and facilitate the selective removal of residual disease in gastrointestinal cancer patients following standard treatments.
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Affiliation(s)
- Arpit Bhargava
- Translational Research Laboratory, School of Biological Sciences, Dr H. S. Gour Central University, Sagar, India
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Patel SP, Osada T, Lyerly HK, Morse MA. Designing effective vaccines for colorectal cancer. Immunotherapy 2015; 6:913-26. [PMID: 25313570 DOI: 10.2217/imt.14.61] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Achieving long-term control of colorectal cancers with therapeutic vaccines that generate potent anti-tumor T cell and antibody responses has been a goal for more than two decades. To date, clinical trials of these vaccines have demonstrated induction of immune responses, but clinical benefit has been limited. Improved vector delivery systems with enhanced immunostimulatory properties, decreased immunogenicity against vector and improved antigen presentation are some of the key features of modern tumor vaccines. Furthermore, an improved understanding of the various immunosuppressive factors in the tumor microenvironment and regional lymph nodes, coupled with a burgeoning ability to impair inhibitory immune synapses, highlights a growing opportunity to induce beneficial antigen-specific responses against tumor. The combination of improved antigenic delivery systems, coupled with therapeutic immune activation, represents state-of-the-art colorectal vaccine design concepts with the goal of augmenting immune responses against tumor and improving clinical outcomes.
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Affiliation(s)
- Sandip P Patel
- UCSD Moores Cancer Center, Division of Medical Oncology, Cancer Immunotherapy Program, 3855 Health Sciences Drive #0987, La Jolla, CA 92093, USA
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Yu L, Lv CY, Yuan AH, Chen W, Wu AW. Significance of the preoperative neutrophil-to-lymphocyte ratio in the prognosis of patients with gastric cancer. World J Gastroenterol 2015; 21:6280-6286. [PMID: 26034363 PMCID: PMC4445105 DOI: 10.3748/wjg.v21.i20.6280] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/02/2015] [Accepted: 03/19/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the significance of the preoperative neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients with gastric cancer (GC).
METHODS: The clinical data of 291 GC patients were analysed retrospectively; these patients were divided into two groups according to their preoperative NLR: a high-NLR group (NLR ≥ 3.5, 131 cases) and a low-NLR group (NLR < 3.5, 160 cases). The clinicopathological characteristics and five-year survival rates of the two groups were compared. The NLR and other clinicopathological factors were subjected to univariate and multivariate survival analysis to evaluate the effects of the NLR on the prognosis of GC patients.
RESULTS: The lowest preoperative NLR among the 291 patients was 0.56, whereas the highest preoperative NLR was 74.5. The mean preoperative NLR was 5.99 ± 8.98. Age, tumour size, T staging, tumour-node-metastasis (TNM) staging and platelet count were significantly different between the high- and low-NLR groups (P < 0.05). The five-year survival rate of the high-NLR group was 17.0%, which was significantly lower than that of the low-NLR group (43.6%; 17.0% vs 43.6%, P < 0.05). The univariate analysis results showed that the five-year survival rate was related to age, tumour size, T staging, N staging, TNM staging, carcinoembryonic antigen value and NLR (P < 0.05). Multivariate analysis results showed that the NLR was an independent risk factor that likely affected the five-year survival rate of GC patients (P = 0.003, HR = 0.626, 95%CI: 0.460-0.852).
CONCLUSION: The preoperative NLR could be used as a prognostic factor for GC patients; in particular, a high NLR corresponded to poor prognosis of GC patients.
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Spolverato G, Maqsood H, Kim Y, Margonis G, Luo T, Ejaz A, Pawlik TM. Neutrophil-lymphocyte and platelet-lymphocyte ratio in patients after resection for hepato-pancreatico-biliary malignancies. J Surg Oncol 2015; 111:868-74. [PMID: 25865111 DOI: 10.1002/jso.23900] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 02/04/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES We sought to determine whether Neutrophil-lymphocyte ratio (NLR) or platelet-lymphocyte ratio (PLR) were associated with outcomes of patients undergoing surgery for a hepatopancreatico-biliary (HPB) malignancy. METHOD Between 2000 and 2013, 452 patients who underwent an HPB procedure for a malignant indication were identified. Clinicopathological characteristics, NLR, and PLR, as well as short- and long-term outcomes were analyzed. High NLR and PLR were classified using a cut-off value of 5 and 190, respectively, based on ROC curve analysis. RESULTS Patients with low versus high NLR and PLR had similar baseline characteristics with regard to performance status and tumor stage (all P > 0.05). Elevated PLR (HR = 1.40) tends to be association with shorter recurrence-free survival (RFS) (P = 0.05), whereas NLR was not a predictor of shorter RFS. Differently, both elevated NLR (HR = 1.94) and PLR (HR = 1.79) were associated with worse overall survival (OS) (both P < 0.05). Patients with NLR ≥5 and those with PLR ≥190 had a significantly shorter OS compared to patients with NLR <5 and PLR <190, respectively (log-rank test, both P < 0.05). Moreover, patients who had both NLR and PLR elevated had worse OS compared to patients with either one or none inflammatory markers elevated (log-rank P = 0.02). CONCLUSION Elevated NLR and PLR were predictors of worse long-term outcome among patients with HPB malignancy undergoing resection.
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Affiliation(s)
- G Spolverato
- The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Markman JL, Shiao SL. Impact of the immune system and immunotherapy in colorectal cancer. J Gastrointest Oncol 2015; 6:208-23. [PMID: 25830040 DOI: 10.3978/j.issn.2078-6891.2014.077] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/20/2014] [Indexed: 12/12/2022] Open
Abstract
The development of cancer is a multi-step process involving the gradual loss of regulation over the growth and functional capabilities of normal cells. Much research has been focused on the numerous cell intrinsic factors that govern this process; however, recent attention has turned to understanding the cell extrinsic factors in the tumor microenvironment that appear equally critical to the progression and treatment of cancer. One critical component of the tumor microenvironment is the immune system and it has become increasingly evident that the immune system plays an integral role in preventing and promoting the development of cancer. Understanding the immune cell types and pathways involved in this process has enabled the development of novel biomarkers for prognosis and accelerated the development of immune-based therapeutics, both of which have the potential to forever change the treatment paradigms for colorectal cancer (CRC). In this review, we discuss the impact of the immune system on the initiation, progression and treatment of cancer, specifically focusing on CRC.
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Affiliation(s)
- Janet L Markman
- 1 Department of Biomedical Sciences, 2 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen L Shiao
- 1 Department of Biomedical Sciences, 2 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Amin M, Lockhart AC. The potential role of immunotherapy to treat colorectal cancer. Expert Opin Investig Drugs 2014; 24:329-44. [PMID: 25519074 DOI: 10.1517/13543784.2015.985376] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Surgery, chemotherapy, radiation therapy and anti-angiogenic therapies form the backbone of treatment for CRC in various stages. Immunotherapy is frequently used either alone or in combination with chemotherapy for the treatment of various cancers such as melanoma, prostate cancer and renal cell cancer. Current CRC research is moving forward to discover ways to incorporate immunotherapies into the treatment of CRC. AREAS COVERED The aim of this review is to summarize the potential role of immunotherapy in CRC. Herein, the authors provide a brief overview of immune modulatory cells, immune surveillance and escape in CRC. They also review vaccine trials in addition to cytokines and monoclonal antibodies. This coverage includes ongoing trials and checkpoint inhibitors such as cytotoxic T lymphocyte antigen-1, programmed cell death-1, and PDL1. EXPERT OPINION Checkpoint inhibitors in combination with either chemotherapy or chemo-antiangiogenic-therapy may represent a future therapeutic approach for CRC incorporating immune system targeting. Given the success of immune-based therapy in other tumor types, the authors anticipate that a similar breakthrough in CRC will be forthcoming.
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Affiliation(s)
- Manik Amin
- Washington University, Siteman Cancer Center , 660 S. Euclid Ave, Box 8056, St. Louis, MO 63110 , USA
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Choi M, Thakur A. Identifying Appropriate Colorectal Cancer-Associated Antigens for the Clinical Trials. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0256-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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40
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Shaib W, Goldstein D, El-Rayes BF. Peptide Vaccines for Treatment of Colon Cancer: Have We Made Progress? CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0250-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Di Caro G, Castino GF, Bergomas F, Cortese N, Chiriva-Internati M, Grizzi F, Marchesi F. Immune-based therapies in pancreatic and colorectal cancers and biomarkers of responsiveness. Expert Rev Anticancer Ther 2014; 14:1219-28. [PMID: 25222571 DOI: 10.1586/14737140.2014.947277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune-based strategies are the most promising treatments to improve cancer disease control. Early clinical trials are ongoing to test the safety and feasibility of immune-based therapies for gastrointestinal cancers. However, to date, immunotherapy has been only an experimental option for these diseases and a better understanding of their molecular, cellular, structural and clinical dissimilarities is crucial in the generation of tailored immunotherapeutic treatments. In this review, we will summarize the key mechanisms that regulate the action of immune system in cancer and the different immune-based approaches aimed at improving disease control in patients with advanced disease. We will then move on to discussing the current immunotherapeutic approaches in two types of gastrointestinal (colo-rectal and pancreatic) cancers, whose immune microenvironment has been lately object of intense analyses and has emerged as an important determinant of clinical outcome.
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Affiliation(s)
- Giuseppe Di Caro
- Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy
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Koido S, Homma S, Okamoto M, Takakura K, Mori M, Yoshizaki S, Tsukinaga S, Odahara S, Koyama S, Imazu H, Uchiyama K, Kajihara M, Arakawa H, Misawa T, Toyama Y, Yanagisawa S, Ikegami M, Kan S, Hayashi K, Komita H, Kamata Y, Ito M, Ishidao T, Yusa SI, Shimodaira S, Gong J, Sugiyama H, Ohkusa T, Tajiri H. Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. Clin Cancer Res 2014; 20:4228-39. [PMID: 25056373 DOI: 10.1158/1078-0432.ccr-14-0314] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We performed a phase I trial to investigate the safety, clinical responses, and Wilms' tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II-restricted epitopes, in combination with chemotherapy. EXPERIMENTAL DESIGN Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II-restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine. RESULTS The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4(+) T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days. CONCLUSIONS The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Clinical Medicine and Research, Departments of Oncology,
| | | | - Masato Okamoto
- Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Masako Mori
- Research and Development Division, Tella Inc., Tokyo
| | | | - Shintaro Tsukinaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Shunichi Odahara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | | | | | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Mikio Kajihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | | | | | | | | | | | | | | | | | | | | | | | - Sei-Ichi Yusa
- Research and Development Division, Tella Inc., Tokyo
| | | | - Jianlin Gong
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Haruo Sugiyama
- Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Osaka, Japan; and
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Hisao Tajiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
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Tumor-associated antigen/IL-21-transduced dendritic cell vaccines enhance immunity and inhibit immunosuppressive cells in metastatic melanoma. Gene Ther 2014; 21:457-67. [PMID: 24572790 DOI: 10.1038/gt.2014.12] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 12/09/2013] [Accepted: 01/10/2014] [Indexed: 12/22/2022]
Abstract
Dendritic cell (DC)-based vaccine approaches are being actively evaluated for developing immunotherapeutic agents against cancers. In this study, we investigated the use of engineered DCs expressing transgenic tumor-associated antigen hgp100 and the regulatory cytokine interleukin-21, namely DC-hgp100/mIL-21, as a therapeutic vaccine against melanoma. Tumor-bearing mice were injected intratumorally with transgenic DCs followed by three booster injections. Transgenic DC-hgp100/mIL-21 showed significant reduction in primary tumor growth and metastasis compared with DC-hgp100 alone and DC-mIL-21 alone. In vivo depletion of specific immune cell types (CD8(+) T, CD4(+) T and Natural killer (NK)-1.1(+) cells) effectively blocked the protective effect of this combinational vaccine. In adoptive transfer experiments, a survival rate of nearly 90% was observed at 60 days post-tumor inoculation for the combinational vaccine group. In contrast, all mice in the DC-hgp100 and DC-mIL-21-only groups died within 43-46 days after tumor challenge. Considerably increased levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte macrophage colony-stimulating factor (GM-CSF) and cytotoxic T lymphocytes (CTLs) were detected with the combination vaccine group compared with other individual treatment groups. In comparison with the DC-hgp100 or mIL-21 groups, the combinational DC-hgp100/mIL-21 vaccine also drastically suppressed the myeloid-derived suppressor cells (MDSCs) and T-regulatory (Treg) cell populations. Our findings suggest that a combinational DC- and gene-based hgp100 and mIL-21 vaccine therapy strategy warrants further evaluation as a clinically relevant cancer vaccine approach for human melanoma patients.
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Mossoba ME, Medin JA. Cancer immunotherapy using virally transduced dendritic cells: animal studies and human clinical trials. Expert Rev Vaccines 2014; 5:717-32. [PMID: 17181444 DOI: 10.1586/14760584.5.5.717] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The immune system uses a process known as 'immunosurveillance' to help prevent the outgrowth of tumors. In cancer immunotherapy, a major goal is for immunity against tumor-associated antigens to be generated or strengthened in patients. To achieve this goal, several approaches have been tested, including the use of highly potent antigen-presenting cells called dendritic cells (DCs), which can activate T cells efficiently. Presentation of peptides derived from tumor antigens on the surface of DCs can stimulate strong antitumor immunity. Using recombinant viral vectors encoding tumor-associated antigens, DCs can be engineered efficiently to express sustained levels of tumor-antigen peptides. This review discusses the effectiveness of virally transduced DCs in treating tumors and generating antigen-specific T-cell responses. It covers mouse and nonhuman primate studies, preclinical in vitro human cell experiments and clinical trials.
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Affiliation(s)
- Miriam E Mossoba
- Department of Medical Biophysics, University of Toronto, 67 College Street, Room 426, Toronto, Ontario, M5G 2MI, Canada.
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Abstract
Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.
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Affiliation(s)
- Mohamed L Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
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Koido S, Ohkusa T, Homma S, Namiki Y, Takakura K, Saito K, Ito Z, Kobayashi H, Kajihara M, Uchiyama K, Arihiro S, Arakawa H, Okamoto M, Gong J, Tajiri H. Immunotherapy for colorectal cancer. World J Gastroenterol 2013; 19:8531-8542. [PMID: 24379570 PMCID: PMC3870498 DOI: 10.3748/wjg.v19.i46.8531] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 10/22/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.
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Status of Active Specific Immunotherapy for Stage II, Stage III, and Resected Stage IV Colon Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0182-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Toomey PG, Vohra NA, Ghansah T, Sarnaik AA, Pilon-Thomas SA. Immunotherapy for gastrointestinal malignancies. Cancer Control 2013; 20:32-42. [PMID: 23302905 DOI: 10.1177/107327481302000106] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the subset of patients undergoing resection, few are cured. There is only a modest improvement in survival with the addition of modalities such as chemotherapy and radiation therapy. Due to an increasing global cancer burden, it is imperative to integrate alternative strategies to improve outcomes. It is well known that cancers possess diverse strategies to evade immune detection and destruction. This has led to the incorporation of various immunotherapeutic strategies, which enable reprogramming of the immune system to allow effective recognition and killing of GI tumors. METHODS A review was conducted of the results of published clinical trials employing immunotherapy for esophageal, gastroesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers. RESULTS Monoclonal antibody therapy has come to the forefront in the past decade for the treatment of colorectal cancer. Immunotherapeutic successes in solid cancers such as melanoma and prostate cancer have led to the active investigation of immunotherapy for GI malignancies, with some promising results. CONCLUSIONS To date, monoclonal antibody therapy is the only immunotherapy approved by the US Food and Drug Administration for GI cancers. Initial trials validating new immunotherapeutic approaches, including vaccination-based and adoptive cell therapy strategies, for GI malignancies have demonstrated safety and the induction of antitumor immune responses. Therefore, immunotherapy is at the forefront of neoadjuvant as well as adjuvant therapies for the treatment and eradication of GI malignancies.
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Affiliation(s)
- Paul G Toomey
- Department of Surgery, USF Health Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Characterization of CD8+ T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mRNA electroporated autologous dendritic cells (TriMixDC-MEL). BIOMED RESEARCH INTERNATIONAL 2013; 2013:976383. [PMID: 23509826 PMCID: PMC3581259 DOI: 10.1155/2013/976383] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 07/21/2012] [Indexed: 12/22/2022]
Abstract
Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8+ T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials.
In 10 out of fourteen (71%) patients screened, CD8+ T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8+ T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8+ T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8+ T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy.
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Aarntzen EH, De Vries IJM, Lesterhuis WJ, Schuurhuis D, Jacobs JF, Bol K, Schreibelt G, Mus R, De Wilt JH, Haanen JB, Schadendorf D, Croockewit A, Blokx WA, Van Rossum MM, Kwok WW, Adema GJ, Punt CJ, Figdor CG. Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination. Cancer Res 2012; 73:19-29. [DOI: 10.1158/0008-5472.can-12-1127] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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