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Fatemi N, Mirbahari SN, Tierling S, Sanjabi F, Shahrivari S, AmeliMojarad M, Amelimojarad M, Mirzaei Rezaei M, Nobaveh P, Totonchi M, Nazemalhosseini Mojarad E. Emerging Frontiers in Colorectal Cancer Therapy: From Targeted Molecules to Immunomodulatory Breakthroughs and Cell-Based Approaches. Dig Dis Sci 2025; 70:919-942. [PMID: 39869166 PMCID: PMC11919954 DOI: 10.1007/s10620-024-08774-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 11/20/2024] [Indexed: 01/28/2025]
Abstract
Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related deaths globally, necessitating urgent advancements in therapeutic approaches. The emergence of groundbreaking therapies, including chimeric antigen receptor-T (CAR-T) cell therapies, oncolytic viruses, and immune checkpoint inhibitors, marks a transformative era in oncology. These innovative modalities, tailored to individual genetic and molecular profiles, hold the promise of significantly enhancing patient outcomes. This comprehensive review explores the latest clinical trials and advancements, encompassing targeted molecular therapies, immunomodulatory agents, and cell-based therapies. By evaluating the strengths, limitations, and potential synergies of these approaches, this research aims to reshape the treatment landscape and improve clinical outcomes for CRC patients, offering new found hope for those who have exhausted conventional options. The culmination of this work is anticipated to pave the way for transformative clinical trials, ushering in a new era of personalized and effective CRC therapy.
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Affiliation(s)
- Nayeralsadat Fatemi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyedeh Nasim Mirbahari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, ACECR, Royan Institute for Reproductive Biomedicine, Tehran, Iran
| | - Sascha Tierling
- Department of Genetics/Epigenetics, Faculty NT, Life Sciences, Saarland University, Saarbrücken, Germany
| | - Fatemeh Sanjabi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical, Tehran, Iran
| | - Shabnam Shahrivari
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical, Tehran, Iran
| | - Mandana AmeliMojarad
- Department of Biology, Faculty of Basic Science, Kharrazi University, Tehran, Iran
| | - Melika Amelimojarad
- Department of Biology, Faculty of Basic Science, Kharrazi University, Tehran, Iran
| | - Meygol Mirzaei Rezaei
- School of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Parsa Nobaveh
- School of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Mehdi Totonchi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, ACECR, Royan Institute for Reproductive Biomedicine, Tehran, Iran
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Yeman St, Chamran Expressway, P.O. Box 19857-17413, Tehran, Iran.
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
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2
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Graciotti M, Kandalaft LE. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat Rev Drug Discov 2025; 24:134-150. [PMID: 39622986 DOI: 10.1038/s41573-024-01081-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 02/06/2025]
Abstract
Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.
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Affiliation(s)
- Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
- Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland.
- AGORA Cancer Research Center, Lausanne, Lausanne, Switzerland.
- Swiss Medical Network, Genolier Innovation Network, Genolier Clinic, Genolier, Switzerland.
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3
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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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Amhis N, Carignan J, Tai LH. Transforming pancreaticobiliary cancer treatment: Exploring the frontiers of adoptive cell therapy and cancer vaccines. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200825. [PMID: 39006944 PMCID: PMC11246060 DOI: 10.1016/j.omton.2024.200825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Pancreaticobiliary cancer, encompassing malignancies of both the pancreatic and biliary tract, presents a formidable clinical challenge marked by a uniformly bleak prognosis. The asymptomatic nature of its early stages often leads to delayed detection, contributing to an unfavorable 5-year overall survival rate. Conventional treatment modalities have shown limited efficacy, underscoring the urgent need for alternative therapeutic approaches. In recent years, immunotherapy has emerged as a promising avenue in the fight against pancreaticobiliary cancer. Strategies such as therapeutic vaccines and the use of tumor-infiltrating lymphocytes have garnered attention for their potential to elicit more robust and durable responses. This review seeks to illuminate the landscape of emerging immunotherapeutic interventions, offering insights from both clinical and research perspectives. By deepening our understanding of pancreaticobiliary cancer and exploring innovative treatment modalities, we aim to catalyze improvements in patient outcomes and quality of life.
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Affiliation(s)
- Nawal Amhis
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Department of Surgery, Division of General Surgery, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Julie Carignan
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
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Somasundaram A, Yeh JJ. Future of Dendritic Cell-Based Approaches in Pancreatic Cancer. J Clin Oncol 2024; 42:3067-3070. [PMID: 38991191 PMCID: PMC11377165 DOI: 10.1200/jco.24.00846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/14/2024] [Accepted: 05/16/2024] [Indexed: 07/13/2024] Open
Affiliation(s)
- Ashwin Somasundaram
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Jen Jen Yeh
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Departments of Surgery and Pharmacology, University of North Carolina, Chapel Hill, NC, USA
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Mahaki H, Ravari H, Kazemzadeh G, Lotfian E, Daddost RA, Avan A, Manoochehri H, Sheykhhasan M, Mahmoudian RA, Tanzadehpanah H. Pro-inflammatory responses after peptide-based cancer immunotherapy. Heliyon 2024; 10:e32249. [PMID: 38912474 PMCID: PMC11190603 DOI: 10.1016/j.heliyon.2024.e32249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/30/2024] [Accepted: 05/30/2024] [Indexed: 06/25/2024] Open
Abstract
Therapeutic vaccinations are designed to prevent cancer by inducing immune responses against tumor antigens. in cancer cells, tumor-associated antigens (TAA) or tumor-specific (mutated) derived peptides are presented within the clefts of main histocompatibility complex (MHC) class I or class II molecules, they either activate cytotoxic T-lymphocytes (CTLs), CD4+ T or CD8+ T lymphocytes, which release cytokines that can suppress tumor cells growth. In cancer immunotherapies, CD8+ T lymphocytes are a major mediator of tumor repression. The effect of peptide-based vaccinations on cytokines in the activating CD8+ T cell against targeted tumor antigens is the subject of this review. It is believed that peptide-based vaccines increased IFN-γ, TNF-α, IL-2, and IL-12, secreting CTL line by interacting with dendritic cell (DC), supposed to stimulate immune system. Additionally, mechanisms of CTL activation and dysfunction were also studied. According to most of the data resulted from in vivo and in vitro research works, it is assumed that peptide-based vaccines increased IFN-γ, TNF-α, IL-2, and IL-12.
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Affiliation(s)
- Hanie Mahaki
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Ravari
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamhossein Kazemzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elham Lotfian
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Reihaneh Alsadat Mahmoudian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Tanzadehpanah
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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7
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Song J, Zhang Y, Zhou C, Zhan J, Cheng X, Huang H, Mao S, Zong Z. The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy. Int Immunopharmacol 2024; 132:112037. [PMID: 38599100 DOI: 10.1016/j.intimp.2024.112037] [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: 02/06/2024] [Revised: 03/24/2024] [Accepted: 04/05/2024] [Indexed: 04/12/2024]
Abstract
Colorectal cancer (CRC) is a typical cancer that accounts for 10% of all new cancer cases annually and nearly 10% of all cancer deaths. Despite significant progress in current classical interventions for CRC, these traditional strategies could be invasive and with numerous adverse effects. The poor prognosis of CRC patients highlights the evident and pressing need for more efficient and targeted treatment. Novel strategies regarding mRNA vaccines for anti-tumor therapy have also been well-developed since the successful application for the prevention of COVID-19. mRNA vaccine technology won the 2023 Nobel Prize in Physiology or Medicine, signaling a new direction in human anti-cancer treatment: mRNA medicine. As a promising new immunotherapy in CRC and other multiple cancer treatments, the mRNA vaccine has higher specificity, better efficacy, and fewer side effects than traditional strategies. The present review outlines the basics of mRNA vaccines and their advantages over other vaccines and informs an available strategy for developing efficient mRNA vaccines for CRC precise treatment. In the future, more exploration of mRNA vaccines for CRC shall be attached, fostering innovation to address existing limitations.
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Affiliation(s)
- Jingjing Song
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Chulin Zhou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; The Second Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Jianhao Zhan
- Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Haoyu Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China
| | - Shengxun Mao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
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8
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Shebbo S, Binothman N, Darwaish M, Niaz HA, Abdulal RH, Borjac J, Hashem AM, Mahmoud AB. Redefining the battle against colorectal cancer: a comprehensive review of emerging immunotherapies and their clinical efficacy. Front Immunol 2024; 15:1350208. [PMID: 38533510 PMCID: PMC10963412 DOI: 10.3389/fimmu.2024.1350208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer globally and presents a significant challenge owing to its high mortality rate and the limitations of traditional treatment options such as surgery, radiotherapy, and chemotherapy. While these treatments are foundational, they are often poorly effective owing to tumor resistance. Immunotherapy is a groundbreaking alternative that has recently emerged and offers new hope for success by exploiting the body's own immune system. This article aims to provide an extensive review of clinical trials evaluating the efficacy of various immunotherapies, including CRC vaccines, chimeric antigen receptor T-cell therapies, and immune checkpoint inhibitors. We also discuss combining CRC vaccines with monoclonal antibodies, delve into preclinical studies of novel cancer vaccines, and assess the impact of these treatment methods on patient outcomes. This review seeks to provide a deeper understanding of the current state of CRC treatment by evaluating innovative treatments and their potential to redefine the prognosis of patients with CRC.
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Affiliation(s)
- Salima Shebbo
- Strategic Research and Innovation Laboratories, Taibah University, Madinah, Saudi Arabia
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Biological Sciences, Beirut Arab University, Debbieh, Lebanon
| | - Najat Binothman
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Manar Darwaish
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hanan A. Niaz
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Rwaa H. Abdulal
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jamilah Borjac
- Department of Biological Sciences, Beirut Arab University, Debbieh, Lebanon
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Clinical Microbiology and Immunology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmad Bakur Mahmoud
- Strategic Research and Innovation Laboratories, Taibah University, Madinah, Saudi Arabia
- College of Applied Medical Sciences, Taibah University, Almadinah Almunawarah, Saudi Arabia
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [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: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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Cheng NC, Vonderheide RH. Immune vulnerabilities of mutant KRAS in pancreatic cancer. Trends Cancer 2023; 9:928-936. [PMID: 37524642 PMCID: PMC10592263 DOI: 10.1016/j.trecan.2023.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 08/02/2023]
Abstract
The 40-year desire to target the mutant Kirsten rat sarcoma (KRAS) gene (mKRAS) therapeutically is being realized with more and more broadly applicable and tumor-specific small-molecule inhibitors. Immunologically, mKRAS has equal desirability as a target. Tumor KRAS signaling plays a large role in shaping the immunosuppressive nature of the tumor microenvironment, especially in pancreatic cancer, leaving mKRAS inhibitors with potentially powerful immune modulatory capabilities that could be exploited in immunological-oncological combinations. mKRAS is itself an immunological antigen, a 'shared neoepitope' linked to the oncogenic process, validated biochemically and immunologically. Novel approaches in the clinic are taking advantage of the fact that mKRAS peptides are naturally processed and presented in tumors by the major histocompatibility complex (MHC).
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Affiliation(s)
- Noah C Cheng
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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11
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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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Alias NAR, Hoo WPY, Siak PY, Othman SS, Mohammed Alitheen NB, In LLA, Abdul Rahim R, Song AAL. Effect of Secretion Efficiency of Mutant KRAS Neoantigen by Lactococcus lactis on the Immune Response of a Mucosal Vaccine Delivery Vehicle Targeting Colorectal Cancer. Int J Mol Sci 2023; 24:8928. [PMID: 37240273 PMCID: PMC10219268 DOI: 10.3390/ijms24108928] [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: 03/31/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Colorectal cancer (CRC) is often caused by mutations in the KRAS oncogene, making KRAS neoantigens a promising vaccine candidate for immunotherapy. Secreting KRAS antigens using live Generally Recognized as Safe (GRAS) vaccine delivery hosts such as Lactococcus lactis is deemed to be an effective strategy in inducing specific desired responses. Recently, through the engineering of a novel signal peptide SPK1 from Pediococcus pentosaceus, an optimized secretion system was developed in the L. lactis NZ9000 host. In this study, the potential of the L. lactis NZ9000 as a vaccine delivery host for the production of two KRAS oncopeptides (mutant 68V-DT and wild-type KRAS) through the use of the signal peptide SPK1 and its mutated derivative (SPKM19) was investigated. The expression and secretion efficiency analyses of KRAS peptides from L. lactis were performed in vitro and in vivo in BALB/c mice. Contradictory to our previous study using the reporter staphylococcal nuclease (NUC), the yield of secreted KRAS antigens mediated by the target mutant signal peptide SPKM19 was significantly lower (by ~1.3-folds) compared to the wild-type SPK1. Consistently, a superior elevation of IgA response against KRAS aided by SPK1 rather than mutant SPKM19 was observed. Despite the lower specific IgA response for SPKM19, a positive IgA immune response from mice intestinal washes was successfully triggered following immunization. Size and secondary conformation of the mature proteins are suggested to be the contributing factors for these discrepancies. This study proves the potential of L. lactis NZ9000 as a host for oral vaccine delivery due to its ability to evoke the desired mucosal immune response in the gastrointestinal tract of mice.
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Affiliation(s)
- Nur Aqlili Riana Alias
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (N.A.R.A.); (S.S.O.); (N.B.M.A.); (R.A.R.)
| | - Winfrey Pui Yee Hoo
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;
| | - Pui Yan Siak
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, Port Dickson 71010, Malaysia;
| | - Siti Sarah Othman
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (N.A.R.A.); (S.S.O.); (N.B.M.A.); (R.A.R.)
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia
| | - Noorjahan Banu Mohammed Alitheen
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (N.A.R.A.); (S.S.O.); (N.B.M.A.); (R.A.R.)
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia
| | - Lionel Lian Aun In
- Department of Biotechnology, Faculty of Applied Sciences, UCSI University Kuala Lumpur, Cheras 56000, Malaysia;
| | - Raha Abdul Rahim
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia; (N.A.R.A.); (S.S.O.); (N.B.M.A.); (R.A.R.)
- National Institutes of Biotechnology Malaysia, Argo-Biotechnology Institute Malaysia Complex, Serdang 43400, Malaysia
| | - Adelene Ai-Lian Song
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia
- Laboratory of Vaccine and Biomolecules, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia
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13
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Tria SM, Burge ME, Whitehall VLJ. The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers. Cancers (Basel) 2023; 15:cancers15082375. [PMID: 37190303 DOI: 10.3390/cancers15082375] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Colorectal cancer is one of the world's most prevalent and lethal cancers. Mutations of the KRAS gene occur in ~40% of metastatic colorectal cancers. While this cohort has historically been difficult to manage, the last few years have shown exponential growth in the development of selective inhibitors targeting KRAS mutations. Their foremost mechanism of action utilizes the Switch II binding pocket and Cys12 residue of GDP-bound KRAS proteins in G12C mutants, confining them to their inactive state. Sotorasib and Adagrasib, both FDA-approved for the treatment of non-small cell lung cancer (NSCLC), have been pivotal in paving the way for KRAS G12C inhibitors in the clinical setting. Other KRAS inhibitors in development include a multi-targeting KRAS-mutant drug and a G12D mutant drug. Treatment resistance remains an issue with combination treatment regimens including indirect pathway inhibition and immunotherapy providing possible ways to combat this. While KRAS-mutant selective therapy has come a long way, more work is required to make this an effective and viable option for patients with colorectal cancer.
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Affiliation(s)
- Simon Manuel Tria
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
| | - Matthew E Burge
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
- School of Medicine, The University of Queensland, Herston, QLD 4029, Australia
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, QLD 4029, Australia
- Department of Medical Oncology, The Prince Charles Hospital, Chermside, QLD 4032, Australia
| | - Vicki L J Whitehall
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
- School of Medicine, The University of Queensland, Herston, QLD 4029, Australia
- Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD 4006, Australia
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14
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Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol 2022; 29:6864-6892. [PMID: 36290818 PMCID: PMC9600738 DOI: 10.3390/curroncol29100541] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 01/13/2023] Open
Abstract
Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Dipanjan Debnath
- Department of Internal Medicine, Medstar Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA
| | - Marion L. Hartley
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Marcus S. Noel
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
- Correspondence:
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15
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Jiang C, Li J, Zhang W, Zhuang Z, Liu G, Hong W, Li B, Zhang X, Chao CC. Potential association factors for developing effective peptide-based cancer vaccines. Front Immunol 2022; 13:931612. [PMID: 35967400 PMCID: PMC9364268 DOI: 10.3389/fimmu.2022.931612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/29/2022] [Indexed: 11/26/2022] Open
Abstract
Peptide-based cancer vaccines have been shown to boost immune systems to kill tumor cells in cancer patients. However, designing an effective T cell epitope peptide-based cancer vaccine still remains a challenge and is a major hurdle for the application of cancer vaccines. In this study, we constructed for the first time a library of peptide-based cancer vaccines and their clinical attributes, named CancerVaccine (https://peptidecancervaccine.weebly.com/). To investigate the association factors that influence the effectiveness of cancer vaccines, these peptide-based cancer vaccines were classified into high (HCR) and low (LCR) clinical responses based on their clinical efficacy. Our study highlights that modified peptides derived from artificially modified proteins are suitable as cancer vaccines, especially for melanoma. It may be possible to advance cancer vaccines by screening for HLA class II affinity peptides may be an effective therapeutic strategy. In addition, the treatment regimen has the potential to influence the clinical response of a cancer vaccine, and Montanide ISA-51 might be an effective adjuvant. Finally, we constructed a high sensitivity and specificity machine learning model to assist in designing peptide-based cancer vaccines capable of providing high clinical responses. Together, our findings illustrate that a high clinical response following peptide-based cancer vaccination is correlated with the right type of peptide, the appropriate adjuvant, and a matched HLA allele, as well as an appropriate treatment regimen. This study would allow for enhanced development of cancer vaccines.
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Affiliation(s)
- Chongming Jiang
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
- *Correspondence: Chongming Jiang, ; Cheng-Chi Chao,
| | - Jianrong Li
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Wei Zhang
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | | | - Geng Liu
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Wei Hong
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Bo Li
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Xiuqing Zhang
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Cheng-Chi Chao
- Department of Pipeline Development, Biomap, Inc, San Francisco, CA, United States
- *Correspondence: Chongming Jiang, ; Cheng-Chi Chao,
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16
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Neoantigen: A Promising Target for the Immunotherapy of Colorectal Cancer. DISEASE MARKERS 2022; 2022:8270305. [PMID: 35211210 PMCID: PMC8863477 DOI: 10.1155/2022/8270305] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 01/28/2022] [Indexed: 02/05/2023]
Abstract
At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such “cold tumors” with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC.
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17
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Hu LF, Lan HR, Huang D, Li XM, Jin KT. Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand? Front Oncol 2021; 11:769305. [PMID: 34888246 PMCID: PMC8649954 DOI: 10.3389/fonc.2021.769305] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.
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Affiliation(s)
- Li-Feng Hu
- Department of Colorectal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dong Huang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xue-Min Li
- Department of Hepatobiliary Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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18
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Abstract
Pancreatic cancer is a kind of digestive tract malignant tumor with a poor prognosis. Radical surgery is the preferred alternative choice for patients with pancreatic cancer, but most patients have no chance of radical surgery when they are diagnosed. At present, a number of studies have been carried out on immunotherapies for pancreatic cancer, mainly including immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy, which are expected to become a new strategy for the treatment of pancreatic cancer, and ultimately achieve the purpose of improving the overall prognosis of patients with pancreatic cancer. In this paper, we summarize the current status of pancreatic cancer immunotherapy and analyze the future trend of immunotherapy for pancreatic cancer.
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Affiliation(s)
- Cheng-Yi Sun
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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19
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Wang D, Zhang H, Xiang T, Wang G. Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients. Front Immunol 2021; 12:762341. [PMID: 34721435 PMCID: PMC8548603 DOI: 10.3389/fimmu.2021.762341] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 09/17/2021] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the treatment outcomes of immunotherapy in microsatellite-stable (MSS) CRC remain unsatisfactory. As the majority of CRC cases display a molecular MSS/mismatch repair-proficient (pMMR) profile, it is particularly meaningful to explore the clinical applications of adaptive immune therapy in MSS CRC patients. In this review, we summarized the therapeutic approaches of adoptive immune therapies, including cytokines, therapeutic cancer vaccines, adoptive T-cell therapy, and immune checkpoint inhibitors, in the treatment of MSS CRCs.
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Affiliation(s)
- Danyang Wang
- Department of Colorectal Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hangyu Zhang
- Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tao Xiang
- Department of Colorectal Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gang Wang
- Department of Anorectal Surgery, Haiyan People’s Hospital, Jiaxing, China
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20
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Tonini V, Zanni M. Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 2021; 27:5851-5889. [PMID: 34629806 PMCID: PMC8475010 DOI: 10.3748/wjg.v27.i35.5851] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.
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Affiliation(s)
- Valeria Tonini
- Department of Medical Sciences and Surgery, University of Bologna- Emergency Surgery Unit, IRCCS Sant’Orsola Hospital, Bologna 40121, Italy
| | - Manuel Zanni
- University of Bologna, Emergency Surgery Unit, IRCCS Sant'Orsola Hospital, Bologna 40121, Italy
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21
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Ghidini M, Fusco N, Salati M, Khakoo S, Tomasello G, Petrelli F, Trapani D, Petrillo A. The Emergence of Immune-checkpoint Inhibitors in Colorectal Cancer Therapy. Curr Drug Targets 2021; 22:1021-1033. [PMID: 33563194 DOI: 10.2174/1389450122666210204204415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/06/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022]
Abstract
Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients' progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Massimiliano Salati
- PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Shelize Khakoo
- Department of Medicine, The Royal Marsden Hospital NHS Foundation Trust, London and Surrey, United Kingdom
| | - Gianluca Tomasello
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fausto Petrelli
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
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22
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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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23
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Curcio C, Brugiapaglia S, Bulfamante S, Follia L, Cappello P, Novelli F. The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer. Molecules 2021; 26:1642. [PMID: 33804240 PMCID: PMC7998946 DOI: 10.3390/molecules26061642] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism-resulting in its increased uptake-and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.
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Affiliation(s)
- Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Laura Follia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Computer Science Department, University of Turin, 10126 Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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24
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Handlos Grauslund J, Holmström MO, Jørgensen NG, Klausen U, Weis-Banke SE, El Fassi D, Schöllkopf C, Clausen MB, Gjerdrum LMR, Breinholt MF, Kjeldsen JW, Hansen M, Koschmieder S, Chatain N, Novotny GW, Petersen J, Kjær L, Skov V, Met Ö, Svane IM, Hasselbalch HC, Andersen MH. Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms. Front Oncol 2021; 11:637420. [PMID: 33718228 PMCID: PMC7952976 DOI: 10.3389/fonc.2021.637420] [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: 12/03/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN. Methods The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446). Results Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines. Conclusion Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.
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Affiliation(s)
- Jacob Handlos Grauslund
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Orebo Holmström
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Nicolai Grønne Jørgensen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Uffe Klausen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Stine Emilie Weis-Banke
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Daniel El Fassi
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Copenhagen University, Copenhagen, Denmark
| | - Claudia Schöllkopf
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Mette Borg Clausen
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | | | | | - Julie Westerlin Kjeldsen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Hansen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Nicolas Chatain
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Guy Wayne Novotny
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Jesper Petersen
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Özcan Met
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.,Institute for Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | | | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.,Institute for Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark
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Khalili JS, Hanson RW, Szallasi Z. In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census. Oncoimmunology 2021; 1:1281-1289. [PMID: 23243591 PMCID: PMC3518500 DOI: 10.4161/onci.21511] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near-term clinical reality. These peptides can be identified for pre-validation by leveraging the results of massive gene sequencing efforts in cancer. In this study, we utilized NetMHC 3.2 to predict nanomolar peptide binding affinity to 57 human HLA-A and B alleles. All peptides were derived from 5,685 missense mutations in 312 genes annotated as functionally relevant in the Cancer Genome Project. Of the 26,672,189 potential 8-11 mer peptide-HLA pairs evaluated, 0.4% (127,800) display binding affinities < 50 nM, predicting high affinity interactions. These peptides can be segregated into two groups based on the binding affinity to HLA proteins relative to germline-encoded sequences: peptides for which both the mutant and wild-type forms are high affinity binders, and peptides for which only the mutant form is a high affinity binder. Current evidence directs the attention to mutations that increase HLA binding affinity, as compared with cognate wild-type peptide sequences, as these potentially are more relevant for vaccine development from a clinical perspective. Our analysis generated a database including all predicted HLA binding peptides and the corresponding change in binding affinity as a result of point mutations. Our study constitutes a broad foundation for the development of personalized peptide vaccines that hone-in on functionally relevant targets in multiple cancers in individuals with diverse HLA haplotypes.
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Affiliation(s)
- Jahan S Khalili
- Departments of Melanoma Medical Oncology and Systems Biology; University of Texas M.D. Anderson Cancer Center; Houston, TX USA
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Holmström MO, Andersen MH. Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens. Cancers (Basel) 2020; 12:cancers12103045. [PMID: 33086698 PMCID: PMC7589254 DOI: 10.3390/cancers12103045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/22/2022] Open
Abstract
The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO+ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.
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Affiliation(s)
- Morten Orebo Holmström
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, DK-2730 Herlev, Denmark;
- Correspondence: ; Tel.: +45-38-682-602
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, DK-2730 Herlev, Denmark;
- Institute for Immunology and Microbiology, Copenhagen University, DK-2200 Copenhagen, Denmark
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27
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Shahnazari M, Samadi P, Pourjafar M, Jalali A. Therapeutic vaccines for colorectal cancer: The progress and future prospect. Int Immunopharmacol 2020; 88:106944. [PMID: 33182032 DOI: 10.1016/j.intimp.2020.106944] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Cancer vaccines are usually derived from the patient's tumor cells or the antigens found on their surface, which may help the immune system to identify and kill these malignant cells. Current focus of many researches is designing vaccines with the hope of triggering the immune system to attack cancer cells in a more effective, reliable and safe manner. Although colorectal cancer (CRC) is recognized as the third leading cause of death by cancer, but significant advances in therapy strategies have been made in recent years, including cancer vaccine. In this review, we present various vaccine platforms that have been used in the border battle against CRC, some of which have been approved for clinical use and some are in late-stage clinical trials. Until September 2020 there is approximately 1940 clinical trials of cancer vaccines on patients with different cancer types, and also many more trials are in the planning stages, which makes it the most important period of therapeutic cancer vaccines studies in the history of the immunotherapy. In cancer vaccines clinical trials, there are several considerations that must be taken into account including engineering of antigen-presenting cells, potential toxicity of antigenic areas, pharmacokinetics and pharmacodynamics of vaccines, and monitoring of the patients' immune response. Therefore, the need to overcome immunosuppression mechanisms/immune tolerance is a critical step for the success of introducing therapeutic vaccines into the widely used drugs on market. In this way, better understanding of neoantigens, tumor immune surveillance escape mechanisms and host-tumor interactions are required to develop more effective and safe cancer vaccines.
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Affiliation(s)
- Mina Shahnazari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Mona Pourjafar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Jalali
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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28
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Wan Y, Zhang Y, Wang G, Mwangi PM, Cai H, Li R. Recombinant KRAS G12D Protein Vaccines Elicit Significant Anti-Tumor Effects in Mouse CT26 Tumor Models. Front Oncol 2020; 10:1326. [PMID: 32903495 PMCID: PMC7435050 DOI: 10.3389/fonc.2020.01326] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Drug development targeting the most frequently mutation G12D of KRAS has great significance. As an attractive immunotherapy, cancer vaccines can overcome binding difficulties of small molecules; however, the weak immunogenicity and production difficulties of reported KRAS mutation vaccines limit their clinical application. To improve antigen-specific immune responses and Anti-Tumor effects on tumors expressing KRAS G12D mutation, we designed recombinant proteins containing KRAS peptide (amino acids 5–21) with G12D (called SP) in two forms: DTT-SP4 and DTSP. DTT-SP4 was constructed by fusing four copies of SP to the C-terminal of the translocation domain of diphtheria toxin (DTT), and DTSP was constructed by grafting SP onto DTT. The two vaccines in combination with aluminum hydroxide (Alum) and cytosine phosphoguanine (CpG) successfully induced conspicuous SP-specific humoral and cellular immune responses, and displayed prominent protective and therapeutic Anti-Tumor effects in mouse CT26 tumor models. Surprisingly, the DTSP-treated group displayed better Anti-Tumor effects in vivo compared with the DTT-SP4-treated and control groups. Moreover, 87.5 and 50% of DTSP-treated mice in the preventive and therapeutic models were tumor free, respectively. Notably, in the DTSP-treated group, the interferon-γ (IFN-γ) expression of T cells in vitro and the T-helper 1 (Th1)–related cytokine expression in tumor tissues indicated that the activated Th1 immune response may be involved in Anti-Tumor activity. Furthermore, DTSP treatment remarkably altered the subpopulation of T cells in splenocytes and tumor-infiltrating lymphocytes. The percentage of effector CD8+ T cells increased, whereas that of immunosuppressive CD4+Foxp3+ T cells remained reduced in the DTSP group. Dramatic tumor-inhibitory effects of DTSP, which is easily prepared, make it a more attractive strategy against KRAS G12D tumors.
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Affiliation(s)
- Yuhua Wan
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Gengchong Wang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Patrick Malonza Mwangi
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Huaman Cai
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Rongxiu Li
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,Shanghai HyCharm Inc., Shanghai, China.,Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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29
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Li QH, Wang YZ, Tu J, Liu CW, Yuan YJ, Lin R, He WL, Cai SR, He YL, Ye JN. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance. Gastroenterol Rep (Oxf) 2020; 8:179-191. [PMID: 32665850 PMCID: PMC7333932 DOI: 10.1093/gastro/goaa026] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/24/2022] Open
Abstract
Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
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Affiliation(s)
- Qing-Hai Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ying-Zhao Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Tu
- Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Chu-Wei Liu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Jie Yuan
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Run Lin
- Department of Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Wei-Ling He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shi-Rong Cai
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Long He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jin-Ning Ye
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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30
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Roy S, Sethi TK, Taylor D, Kim YJ, Johnson DB. Breakthrough concepts in immune-oncology: Cancer vaccines at the bedside. J Leukoc Biol 2020; 108:1455-1489. [PMID: 32557857 DOI: 10.1002/jlb.5bt0420-585rr] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 04/15/2020] [Accepted: 04/18/2020] [Indexed: 12/11/2022] Open
Abstract
Clinical approval of the immune checkpoint blockade (ICB) agents for multiple cancer types has reinvigorated the long-standing work on cancer vaccines. In the pre-ICB era, clinical efforts focused on the Ag, the adjuvants, the formulation, and the mode of delivery. These translational efforts on therapeutic vaccines range from cell-based (e.g., dendritic cells vaccine Sipuleucel-T) to DNA/RNA-based platforms with various formulations (liposome), vectors (Listeria monocytogenes), or modes of delivery (intratumoral, gene gun, etc.). Despite promising preclinical results, cancer vaccine trials without ICB have historically shown little clinical activity. With the anticipation and expansion of combinatorial immunotherapeutic trials with ICB, the cancer vaccine field has entered the personalized medicine arena with recent advances in immunogenic neoantigen-based vaccines. In this article, we review the literature to organize the different cancer vaccines in the clinical space, and we will discuss their advantages, limits, and recent progress to overcome their challenges. Furthermore, we will also discuss recent preclinical advances and clinical strategies to combine vaccines with checkpoint blockade to improve therapeutic outcome and present a translational perspective on future directions.
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Affiliation(s)
- Sohini Roy
- Department of Otolaryngology - Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Tarsheen K Sethi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - David Taylor
- Department of Otolaryngology - Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Young J Kim
- Department of Otolaryngology - Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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31
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Schizas D, Charalampakis N, Kole C, Economopoulou P, Koustas E, Gkotsis E, Ziogas D, Psyrri A, Karamouzis MV. Immunotherapy for pancreatic cancer: A 2020 update. Cancer Treat Rev 2020; 86:102016. [PMID: 32247999 DOI: 10.1016/j.ctrv.2020.102016] [Citation(s) in RCA: 288] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic adenocarcinoma (PAC) is associated with extremely poor prognosis and remains a lethal malignancy. The main cure for PAC is surgical resection. Further treatment modalities, such as surgery, chemotherapy, radiotherapy and other locoregional therapies provide low survival rates. Currently, many clinical trials seek to assess the efficacy of immunotherapeutic strategies in PAC, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, combinations with other immunotherapeutic agents, chemoradiotherapy or other molecularly targeted agents; however, none of these studies have shown practice changing results. There seems to be a synergistic effect with increased response rates when a combinatorial approach of immunotherapy in conjunction with other modalities is being exploited. In this review, we illustrate the current role of immunotherapy in PAC.
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Affiliation(s)
- Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | | | - Christo Kole
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Panagiota Economopoulou
- Department of Internal Medicine, Section of Medical Oncology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthymios Gkotsis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Dimitrios Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Amanda Psyrri
- Department of Internal Medicine, Section of Medical Oncology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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32
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Immunotherapy in gastrointestinal cancer: The current scenario and future perspectives. Cancer Treat Rev 2020; 88:102030. [PMID: 32505807 DOI: 10.1016/j.ctrv.2020.102030] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 02/06/2023]
Abstract
Gastrointestinal cancers include colorectal, gastric, oesophageal, pancreatic and liver cancers. They continue to be a significant cause of mortality and morbidity worldwide. Current treatment strategies include chemotherapy, surgery, radiotherapy and targeted therapies. Immunotherapy has recently been incorporated in treatment regimens for some gastrointestinal malignancies and research into different immune modifying treatments is being carried out in this context. Approaches to immune modulation such as vaccination, adoptive cell therapy and checkpoint inhibition have shown varying clinical benefit, with most of the benefit seen in checkpoint inhibition. This review summarises recent advances and future direction of immunotherapy in patients with gastrointestinal malignancies.
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Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines 2020; 19:163-173. [PMID: 32174221 DOI: 10.1080/14760584.2020.1733420] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Mutant KRAS is a genetic driver of multiple cancers that has challenged clinical anti-cancer therapeutics in the last 3 decades. Neo-antigens encoded by KRAS mutations have been identified as tumor-specific with high immunogenicity and can be used to deliver precision cancer vaccines to promote anti-tumor immune responses. KRAS mutation-based cancer vaccines have produced encouraging preclinical and clinical results. Cancer vaccines represent a promising approach to treat KRAS-driven cancers.Areas covered: In this review, we summarize the development and progress of vaccines targeting KRAS and evaluate their potential benefits and obstacles in the current landscape of therapy for KRAS-driven cancers.Expert opinion: KRAS mutation-based cancer vaccines can induce immunogenicity in patients with KRAS-driven cancers. However, the mechanisms of tumor suppression including cellular and molecular factors within the tumor microenvironment may limit vaccine efficacy. Combining KRAS-driven therapeutic cancer vaccines with other methods and adjuvants can circumvent immunosuppression and promote therapeutic successes.
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Affiliation(s)
- Ying Zhang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jin-An Ma
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hai-Xia Zhang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yu-Na Jiang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Hao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Shen Y, Wei X, Jin S, Wu Y, Zhao W, Xu Y, Pan L, Zhou Z, Chen S. TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation. Asian J Pharm Sci 2020; 15:777-785. [PMID: 33363632 PMCID: PMC7750800 DOI: 10.1016/j.ajps.2020.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/29/2019] [Accepted: 01/22/2020] [Indexed: 12/22/2022] Open
Abstract
Limited clinical application of antibody-drug conjugates (ADCs) targeting tumor associated antigens (TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens (TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I (HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.
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Affiliation(s)
- Ying Shen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaoyue Wei
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Huabo Biopharm Co., Ltd., Shanghai 201203, China
| | - Shijie Jin
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yue Wu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenbin Zhao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yingchun Xu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Liqiang Pan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhan Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Shuqing Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020; 17:153-168. [PMID: 32005945 DOI: 10.1038/s41575-019-0245-4] [Citation(s) in RCA: 446] [Impact Index Per Article: 89.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2019] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second most common cause of death within the next 10 years. The prognosis for this disease is poor despite diagnostic progress and new chemotherapeutic regimens. The oncogenic KRAS mutation is the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, which acts as a molecular switch to activate various intracellular signalling pathways and transcription factors inducing cell proliferation, migration, transformation and survival. Several laboratory methods have been developed to detect KRAS mutations in biological samples, including digital droplet PCR (which displays high sensitivity). Clinical studies have revealed that a KRAS mutation assay in fine-needle aspiration material combined with cytopathology increases the sensitivity, accuracy and negative predictive value of cytopathology for a positive diagnosis of pancreatic cancer. In addition, the presence of KRAS mutations in serum and plasma (liquid biopsies) correlates with a worse prognosis. The presence of mutated KRAS can also have therapeutic implications, whether at the gene level per se, during its post-translational maturation, interaction with nucleotides and after activation of the various oncogenic signals. Further pharmacokinetic and toxicological studies on new molecules are required, especially small synthetic molecules, before they can be used in the therapeutic arsenal for pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Louis Buscail
- Department of Gastroenterology, University of Toulouse III, Rangueil Hospital, Toulouse, France. .,INSERM UMR 1037, Toulouse Centre for Cancer Research, University of Toulouse III, Toulouse, France.
| | - Barbara Bournet
- Department of Gastroenterology, University of Toulouse III, Rangueil Hospital, Toulouse, France.,INSERM UMR 1037, Toulouse Centre for Cancer Research, University of Toulouse III, Toulouse, France
| | - Pierre Cordelier
- INSERM UMR 1037, Toulouse Centre for Cancer Research, University of Toulouse III, Toulouse, France
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Parlane NA, Wedlock DN, Han JH, Park JH. Heterologous peptide display on chromatin nanofibers: A new strategy for peptide vaccines. Biochem Biophys Res Commun 2020; 524:825-831. [PMID: 32037086 DOI: 10.1016/j.bbrc.2020.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/02/2020] [Indexed: 12/22/2022]
Abstract
Chromatin organization starts from a "beads-on-a string" 10 nm fiber, a basic nucleosomal structure consisting of DNA and core histones. Given its regular nucleosome array on DNA backbone where N-terminal tails of each histone are exposed on the surface of chromatin fiber, we hypothesized that chromatin can be utilized as a heterologous peptide carrier to elicit a peptide-specific immune response. The plasmid DNA containing the Widom's clone 601 sequence and the recombinant chimeric histones containing the peptide derived from ras oncogene (G12V) were used to assemble the chromatin fiber in vitro. The immunogenicity of the assembled chromatin was tested in mice as a single vaccine component or formulated with adjuvants. G12V tagged-chromatin co-administered with adjuvants induced higher antibody responses against the G12V peptide than vaccination with adjuvant alone, while chimeric histones did not generate a significant antibody response. Interestingly, splenocytes from mice vaccinated with the G12V tagged-chromatin vaccine did not generate significant antigen-specific cytokine responses. Our studies suggest that chromatin can be utilized as an effective carrier of antigenic peptides for inducing specific antibody responses.
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Affiliation(s)
- Natalie A Parlane
- AgResearch, Hopkirk Research Institute, Palmerston North, New Zealand
| | - D Neil Wedlock
- AgResearch, Hopkirk Research Institute, Palmerston North, New Zealand
| | - Jun-Hee Han
- EpiCentre, School of Veterinary Science, Massey University, New Zealand
| | - Jeong Hyeon Park
- School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.
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Blaeschke F, Paul MC, Schuhmann MU, Rabsteyn A, Schroeder C, Casadei N, Matthes J, Mohr C, Lotfi R, Wagner B, Kaeuferle T, Feucht J, Willier S, Handgretinger R, StevanoviĆ S, Lang P, Feuchtinger T. Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy. Cytotherapy 2019; 21:973-986. [PMID: 31351799 DOI: 10.1016/j.jcyt.2019.06.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/08/2019] [Accepted: 06/28/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity. METHODS We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8+ cytotoxic T cells in vitro. RESULTS Despite low mutational tumor burden, at least two immunogenic tumor-specific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants. CONCLUSION Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.
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Affiliation(s)
- Franziska Blaeschke
- Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Milan Cedric Paul
- Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Martin Ulrich Schuhmann
- Division of Pediatric Neurosurgery, Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany
| | - Armin Rabsteyn
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tübingen, Germany
| | - Christopher Schroeder
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Nicolas Casadei
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Jakob Matthes
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Christopher Mohr
- Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany; Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany
| | - Ramin Lotfi
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Württemberg-Hessen, Ulm, Germany
| | - Beate Wagner
- Department of Transfusion Medicine and Hemostaseology, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany
| | - Theresa Kaeuferle
- Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Judith Feucht
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tübingen, Germany; Memorial Sloan Kettering Cancer Center, Center for Cell Engineering, New York, New York, USA
| | - Semjon Willier
- Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Rupert Handgretinger
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tübingen, Germany
| | - Stefan StevanoviĆ
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Peter Lang
- Department of General Pediatrics, Hematology/Oncology, University Children's Hospital, Tübingen, Germany
| | - Tobias Feuchtinger
- Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
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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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Wang HC, Hung WC, Chen LT, Pan MR. From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis. Int J Mol Sci 2018; 19:E3584. [PMID: 30428588 PMCID: PMC6274888 DOI: 10.3390/ijms19113584] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/09/2018] [Accepted: 11/11/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor cells and is a new strategy for cancer treatment. The anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies pembrolizumab and nivolumab have been approved for cancer therapy in different countries. However, the results of immunotherapy on PDAC are unsatisfactory. The low response rate may be due to poor immunogenicity with low tumor mutational burden in pancreatic cancer cells and desmoplasia that prevents the accumulation of immune cells in tumors. The immunosuppressive tumor microenvironment in PDAC is important in tumor progression and treatment resistance. Switching from an immune tolerance to immune activation status is crucial to overcome the inability of self-defense in cancer. Therefore, thoroughly elucidation of the roles of various immune-related factors, tumor microenvironment, and tumor cells in the development of PDAC may provide appropriate direction to target inflammatory pathway activation as a new therapeutic strategy for preventing and treating this cancer.
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Affiliation(s)
- Hui-Ching Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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40
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Formaldehyde-mediated peptide coupling for the titration of epitope-specific antibody in an ELISA format. J Immunol Methods 2018; 461:106-109. [DOI: 10.1016/j.jim.2018.06.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/05/2018] [Accepted: 06/29/2018] [Indexed: 02/08/2023]
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Pilla L, Ferrone S, Maccalli C. Methods for improving the immunogenicity and efficacy of cancer vaccines. Expert Opin Biol Ther 2018; 18:765-784. [PMID: 29874943 PMCID: PMC8670419 DOI: 10.1080/14712598.2018.1485649] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 06/04/2018] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Cancer vaccines represent one of the oldest immunotherapy strategies. A variety of tumor-associated antigens have been exploited to investigate their immunogenicity as well as multiple strategies for vaccine administration. These efforts have led to the development of several clinical trials in tumors with different histological origins to test the clinical efficacy of cancer vaccines. However, suboptimal clinical results have been reported mainly due to the lack of optimized strategies to induce strong and sustained systemic tumor antigen-specific immune responses. AREAS COVERED We provide an overview of different types of cancer vaccines that have been developed and used in the context of clinical studies. Moreover, we review different preclinical and clinical strategies pursued to enhance the immunogenicity, stability, and targeting at tumor site of cancer vaccines. EXPERT OPINION Additional and appropriate preclinical studies are warranted to optimize the immunogenicity and delivery of cancer vaccines. The appropriate choice of target antigens is challenging; however, the exploitation of neoantigens generated from somatic mutations of tumor cells represents a promising approach to target highly immunogenic tumor-specific antigens. Remarkably, the investigation of the combination of cancer vaccines with immunomodulating agents able to skew the tumor microenvironment from immunosuppressive to immunostimulating will dramatically improve their clinical efficacy.
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Affiliation(s)
- Lorenzo Pilla
- Medical Oncology Unit, San Gerardo Hospital, Monza, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina Maccalli
- Clinical Research Center, Division of Translational Medicine, Sidra Medicine, Doha, Qatar
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42
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Morrison AH, Byrne KT, Vonderheide RH. Immunotherapy and Prevention of Pancreatic Cancer. Trends Cancer 2018; 4:418-428. [PMID: 29860986 PMCID: PMC6028935 DOI: 10.1016/j.trecan.2018.04.001] [Citation(s) in RCA: 321] [Impact Index Per Article: 45.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 12/16/2022]
Abstract
Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer's lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.
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Affiliation(s)
- Alexander H Morrison
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA
| | - Katelyn T Byrne
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19014, USA
| | - Robert H Vonderheide
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19014, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19014, USA.
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Rosenberg A, Mahalingam D. Immunotherapy in pancreatic adenocarcinoma-overcoming barriers to response. J Gastrointest Oncol 2018; 9:143-159. [PMID: 29564181 PMCID: PMC5848027 DOI: 10.21037/jgo.2018.01.13] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 12/28/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) remains one of the leading causes of cancer-related death. Despite multiple advances in targeted and immune therapies, the 5-year survival in advanced PAC remains poor. In this review, we discuss some of the unique aspects of the tumor microenvironment (TME) in PAC that may contribute to its resistance to immune therapies, as well as opportunities to potentially overcome some of these inherent barriers. Furthermore, we discuss strategies to enable immune therapies in PAC such as cytotoxic chemotherapy and radiation therapy, cancer vaccines, cytokine based therapy, oncolytic viruses, and adoptive T-cell therapy. Finally, we address a variety of targeted therapies as a strategy to further amplify immune responses in PAC.
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Affiliation(s)
- Ari Rosenberg
- Department of Medicine, Northwestern University, Chicago, IL, USA
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Obeid JM, Kunk PR, Zaydfudim VM, Bullock TN, Slingluff CL, Rahma OE. Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time? Cancer Immunol Immunother 2018; 67:161-174. [PMID: 29052780 PMCID: PMC11028155 DOI: 10.1007/s00262-017-2082-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 10/15/2017] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver's inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions.
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Affiliation(s)
- Joseph M Obeid
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Paul R Kunk
- Division of Hematology-Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | | | - Timothy N Bullock
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Craig L Slingluff
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Osama E Rahma
- Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, 450 Brookline Avenue, M1B13, Boston, MA, 02215, USA.
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Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy. Cancers (Basel) 2018; 10:cancers10010006. [PMID: 29301364 PMCID: PMC5789356 DOI: 10.3390/cancers10010006] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 12/22/2017] [Accepted: 12/27/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8⁺ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.
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Beatty GL, Eghbali S, Kim R. Deploying Immunotherapy in Pancreatic Cancer: Defining Mechanisms of Response and Resistance. Am Soc Clin Oncol Educ Book 2017; 37:267-278. [PMID: 28561678 DOI: 10.1200/edbk_175232] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The immune reaction to pancreatic ductal adenocarcinoma (PDAC) is a strong prognostic determinant of clinical outcomes and may be a promising therapeutic target. We use multiplex immunohistochemistry to illustrate distinct patterns of T-cell and myeloid cell infiltration seen in PDAC that have therapeutic implications and discuss the current state of immunotherapy in this disease. Based on collective findings from clinical and preclinical studies, two conceptual models have emerged for applying immunotherapy in PDAC that involve (1) restoring elements of T-cell immunosurveillance and (2) redirecting myeloid cells to condition tumors with increased sensitivity to cytotoxic therapies. Overall, the success of immunotherapy in PDAC will most likely rely on strategic combinations of therapies that are informed by well-designed correlative analyses that consider the spatial heterogeneity of immune responses detected in malignant tissues.
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Affiliation(s)
- Gregory L Beatty
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Shabnam Eghbali
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Rebecca Kim
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Pan J, Zhang Q, Sei S, Shoemaker RH, Lubet RA, Wang Y, You M. Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. Oncotarget 2017; 8:82689-82699. [PMID: 29137294 PMCID: PMC5669920 DOI: 10.18632/oncotarget.19831] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 03/01/2017] [Indexed: 12/22/2022] Open
Abstract
Lung cancer remains the leading cause of cancer death worldwide. Mutations in KRAS are detected in up to 30% of lung cancer cases. No effective therapies specifically targeting mutant KRAS have been developed. Vaccination against KRAS mutants is one of the venues of active exploration. The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multipeptide vaccine targeting multiple epitopes of the KRAS molecule. The formulated vaccine contained top four peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. The multipeptide KRAS vaccine was tested in an inducible CCSP-TetO-KRASG12D mouse model, where the vaccine was administered prior to activating the mutant KRAS protein. The KRAS peptide vaccine exhibited striking efficacy, reducing tumor number and tumor burden by >80% when compared with adjuvant alone. Splenocytes collected from vaccinated animals showed a robust immunologic response to the immunizing peptides. Furthermore, in vitro stimulation of these splenocytes by the vaccinated peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. The multipeptide KRAS vaccine was immunogenic and efficacious in the primary prevention of KRAS-induced lung cancer, indicating that the approach potentially can be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities.
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Affiliation(s)
- Jing Pan
- Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Qi Zhang
- Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Shizuko Sei
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Robert H Shoemaker
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Ronald A Lubet
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Yian Wang
- Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Ming You
- Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
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Abstract
The study of oncogenic RAS mutations has led to crucial discoveries regarding cancer molecular biology and behavior and has been integral in shaping the era of targeted cancer therapy. RAS mutations are one of the most common oncogenic drivers in human cancer, and intense efforts to find a clinically effective inhibitor are ongoing. Despite these efforts, targeting RAS mutations has remained elusive, so much so that some have termed oncogenic RAS mutations as "undruggable." In this review, we will summarize current understanding of RAS biology, explore strategies to inhibit RAS oncoproteins and its downstream effectors, and discuss recently described complexities that have shed new light on this pursuit.
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Thind K, Padrnos LJ, Ramanathan RK, Borad MJ. Immunotherapy in pancreatic cancer treatment: a new frontier. Therap Adv Gastroenterol 2017; 10:168-194. [PMID: 28286568 PMCID: PMC5330603 DOI: 10.1177/1756283x16667909] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy. Novel therapies targeting the tumor microenvironment with an aim to decrease this resistance, improve immune tolerance and increase the efficacy of the current treatment have shown some promising preliminary results in preclinical and clinical trials. We review the current advances in the field of immunotherapy and their effectiveness as a potential treatment strategy in the pancreatic cancer.
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Affiliation(s)
- Komal Thind
- Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, USA
| | - Leslie J. Padrnos
- Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | - Mitesh J. Borad
- Division of Hematology/Oncology, Mayo Clinic Arizona, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA
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Pardieck IN, Jawahier PA, Swets M, van de Velde CJH, Kuppen PJK. Novel avenues in immunotherapies for colorectal cancer. Expert Rev Gastroenterol Hepatol 2016; 10:465-80. [PMID: 26582071 DOI: 10.1586/17474124.2016.1122522] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Since it is known that the immune system affects tumor growth, it has been studied if immunotherapy can be developed to combat cancer. While some successes have been claimed, the increasing knowledge on tumor-immune interactions has, however, also shown the limitations of this approach. Tumors may show selective outgrowth of cells escaped from immune control. Escape variants arise spontaneously due to the genetically instable nature of tumor cells. This is one of the most obvious limitations of cancer immunotherapy. However, new therapies are becoming available, designed to respond to tumor-immune escape.
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Affiliation(s)
- Iris N Pardieck
- a Department of Surgery , Leiden University Medical Center , Leiden , The Netherlands
| | - Priscilla A Jawahier
- a Department of Surgery , Leiden University Medical Center , Leiden , The Netherlands
| | - Marloes Swets
- a Department of Surgery , Leiden University Medical Center , Leiden , The Netherlands
| | | | - Peter J K Kuppen
- a Department of Surgery , Leiden University Medical Center , Leiden , The Netherlands
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