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He Y, Kong J, Wang Z, Zhang Y, Qing T, Xie F, Chen T, Han J. Development of a novel molecular probe for visualizing mesothelin on the tumor via positron emission tomography. Eur J Nucl Med Mol Imaging 2025; 52:2605-2616. [PMID: 39878895 DOI: 10.1007/s00259-025-07087-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/12/2025] [Indexed: 01/31/2025]
Abstract
OBJECTIVES Mesothelin (MSLN) is an antigen that is overexpressed in various cancers, and its interaction with tumor-associated cancer antigen 125 plays a multifaceted role in tumor metastasis. The serum MSLN expression level can be detected using enzyme-linked immunosorbent assay; however, non-invasive visualization of its expression at the tumor site is currently lacking. Therefore, the aim of this study was to develop a molecular probe for imaging MSLN expression through positron emission tomography (PET). METHODS VHH 269-H4 was obtained via immunization of llama using a fragment of MSLN from residue 360 to residue 597. S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to VHH 269-H4 to yield precursor NOTA 269-H4 for radiolabeling. The chelator-to-VHH ratio was determined by mass spectrometry. The binding kinetics of VHH 269-H4 and NOTA 269-H4 were measured by surface plasmon resonance. Flow cytometry was carried out using the anti-mesothelin monoclonal antibody Anetumab to select MSLN-positive and MSLN-negative cell lines. After radiolabeling, the radiochemical purity and in vitro stability were tested by radio-thin-layer chromatography and size exclusion chromatography, respectively. A saturation binding assay was conducted to measure the dissociation constant (Kd) of [68Ga]Ga-NOTA-269-H4. By mircoPET/CT imaging and biodistribution studies, the in vivo performances of the novel tracer were investigated in NCG mice bearing OVCAR-8, SKOV-3, or patient-derived xenografts. RESULTS VHH 269-H4 targeting MSLN was obtained with a Kd value of 0.3 nM. After conjugation, approximately 27% and 3.2% of VHH were coupled to one and two NOTA chelators, respectively. This yielded precursor NOTA 269-H4 with a Kd value of 1.1 nM. The radiochemistry was accomplished with moderate radiochemical yields (34 ± 14%, n = 9, decay-corrected). [68Ga]Ga-NOTA-269-H4 was obtained with high radiochemical purity (> 99%), and was stable after 90 min incubation at room temperature. The binding affinity of the radioligand towards MSLN was kept in the nanomolar range. Flow cytometry revealed that OVCAR-8 cells possess a high level of MSLN expression, while MSLN expression on SKOV-3 cells was negligible. Consistently, in microPET/CT imaging, [68Ga]Ga-NOTA-269-H4 demonstrated clear tumor visualization using NCG mice bearing OVCAR-8 xenografts, but no radioactivity accumulation was observed in SKOV-3 xenografts, suggesting a high specificity of the tracer in vivo. In biodistribution studies, [68Ga]Ga-NOTA-269-H4 displayed radioactivity accumulation of 2.93 ± 0.39%ID/g in OVCAR-8 xenografts at 30 min post-injection, and the highest tumor-to-blood ratio (~ 3) was achieved at 90 min post-injection. In NCG mice bearing patient-derived xenografts, [68Ga]Ga-NOTA-269-H4 was able to noninvasively detect MSLN expression via microPET/CT imaging. CONCLUSIONS To our knowledge, our studies achieved the first-time to non-invasively detect MSLN expression clearly using a single domain antibody fragment. To sum up, [68Ga]Ga-NOTA-269-H4 is a highly promising PET probe to visualize MSLN expression in vivo and holds great potential to monitor MSLN expression during tumor development.
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Affiliation(s)
- Yingfang He
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China
| | - Jinping Kong
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, China
| | - Ze Wang
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China
| | - Yu Zhang
- Department of Translational Medicine, Zentera Therapeutics, 183 Hongqiao Road, Shanghai, China
| | - Tingting Qing
- Department of Translational Medicine, Zentera Therapeutics, 183 Hongqiao Road, Shanghai, China
| | - Fang Xie
- Department of Nuclear Medicine & PET center, Huashan Hospital, Fudan University, 200233, Shanghai, China
| | - Tengxiang Chen
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, China.
| | - Junbin Han
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China.
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Rahimi A, Baghernejadan Z, Hazrati A, Malekpour K, Samimi LN, Najafi A, Falak R, Khorramdelazad H. Combination therapy with immune checkpoint inhibitors in colorectal cancer: Challenges, resistance mechanisms, and the role of microbiota. Biomed Pharmacother 2025; 186:118014. [PMID: 40157004 DOI: 10.1016/j.biopha.2025.118014] [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: 01/08/2025] [Revised: 03/17/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
Colorectal cancer (CRC) is still one of the leading causes of cancer deaths worldwide. Even though there has been progress in cancer immunotherapy, the results of applying immune checkpoint inhibitors (ICIs) have been unsatisfactory, especially in microsatellite stable (MSS) CRC. Single-agent ICIs that target programmed cell death-1 (PD-1)/ PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell Ig- and mucin-domain-containing molecule-3 (TIM-3), and lymphocyte activation gene (LAG)-3 have emerged as having specific benefits. However, many primary and secondary resistance mechanisms are available in the tumor microenvironment (TME) that prevent it from happening. Combination strategies, such as the use of anti-PD-1 and anti-CTLA-4, can be effective in overcoming these resistance pathways, but toxicities remain a significant concern. Moreover, ICIs have been integrated with various treatment modalities, including chemotherapy, radiotherapy, antibiotics, virotherapy, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, and heat shock protein 90 (HSP90) inhibitors. The outcomes observed in both preclinical and clinical settings have been encouraging. Interestingly, manipulating gut microbiota via fecal microbiota transplantation (FMT) has been identified as a new strategy to increase the efficacy of immunotherapy in CRC patients. Therefore, integrating ICIs with other treatment approaches holds promise in enhancing the prognosis of CRC patients. This review focuses on the unmet need for new biomarkers to select patients for combination therapies and the ongoing work to overcome resistance and immune checkpoint blockade.
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Affiliation(s)
- Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Baghernejadan
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Gutiu AG, Zhao L, Marrah AJ, Maher AJ, Voss BB, Mayberry TG, Cowan BC, Wakefield MR, Fang Y. Promising immunotherapeutic treatments for colon cancer. Med Oncol 2025; 42:175. [PMID: 40266497 DOI: 10.1007/s12032-025-02724-2] [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: 01/11/2025] [Accepted: 04/14/2025] [Indexed: 04/24/2025]
Abstract
Colon cancer continues to predominate as one of the most common causes of morbidity and mortality worldwide due to its subtle symptomology and multifactorial etiology. Currently, the standard treatment approach involves surgical resection for localized tumors and adjuvant chemotherapy (AC) for cancers that have spread or invaded locally. Unfortunately, this treatment strategy may not be effective for advanced, metastatic stages of the disease or in instances of recurrence. However, advancements in immunotherapy have demonstrated promising results in the field of medical oncology, which could redefine the way patients and clinicians view the disease. These treatments have shown benefit and have the potential to be superior to the current interventions available for afflicted patients. The application of immunotherapy in conjunction with traditional treatments may improve the outcomes of patients suffering from colon cancer and decrease the burden this disease has on patients. Furthermore, more effective treatments in the form of conjunction immunological, surgical, and chemotherapeutic techniques may shorten treatment courses and lead to better long-term effects. This review paper investigates immunotherapeutic interventions for colon cancer, which include immune checkpoint inhibitors, oncolytic virotherapy, cancer vaccines, cytokine therapy, and CAR-T. Such a study might provide more information for clinicians to treat patients with colon cancer in the advanced stages or in recurrence.
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Affiliation(s)
- Arturo G Gutiu
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA
| | - Lei Zhao
- Department of Respiratory Medicine, The 2nd People's Hospital of Hefei and Hefei Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Austin J Marrah
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Austin J Maher
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Brady B Voss
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Trenton G Mayberry
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Braydon C Cowan
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, West Des Moines, IA, 50266, USA.
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Liu C, Liu N, Zhang T, Tu Y. Adoptive immune cell therapy for colorectal cancer. Front Immunol 2025; 16:1557906. [PMID: 40236691 PMCID: PMC11996668 DOI: 10.3389/fimmu.2025.1557906] [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: 01/09/2025] [Accepted: 02/28/2025] [Indexed: 04/17/2025] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide, with limited options for patients at advanced stages. Immunotherapy, particularly immune cell-based therapies, has gained significant attention as an innovative approach for targeting CRC. This review summarizes the progress in various immune cell therapies, including DC vaccine, CAR/TCR-T cells, CAR-NK cells et al, each engineered to recognize and attack cancer cells expressing specific antigens. CAR-T cell therapy, which has been successful in hematologic cancers, faces challenges in CRC due to the solid tumor microenvironment, which limits cell infiltration and persistence. CAR-NK cells, CAR-M and CAR-γδ T cells, however, offer alternative strategies due to their unique properties, such as the ability to target tumor cells without prior sensitization and a lower risk of inducing severe cytokine release syndrome. Recent advances in lentiviral transduction have enabled effective expression of CARs on NK and γδ T cells, providing promising preclinical results in CRC models. This review explores the mechanisms, tumor targets, preclinical studies, and early-phase clinical trials of these therapies, addressing key challenges such as enhancing specificity to tumor antigens and overcoming the immunosuppressive tumor microenvironment. The potential of combination therapies, including immune checkpoint inhibitors and cytokine therapy, is also discussed some as a means to improve the effectiveness of immune cell-based treatments for CRC. Continued research is essential to translate these promising approaches into clinical settings, offering new hope for CRC patients.
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Affiliation(s)
- Chenxiao Liu
- Guangdong Province Science and Technology Expert Workstation, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
| | - Nan Liu
- Guangdong Province Science and Technology Expert Workstation, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, China
| | - Tongcun Zhang
- Guangdong Province Science and Technology Expert Workstation, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, China
| | - Yanyang Tu
- Science Research Center, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
- Huizhou Central People’s Hospital Academy of Medical Sciences, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
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Ouladan S, Orouji E. Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy. J Clin Oncol 2025; 43:994-1005. [PMID: 39805063 PMCID: PMC11895826 DOI: 10.1200/jco-24-02081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/22/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Colorectal cancer (CRC) remains a major global health burden, being one of the most prevalent cancers with high mortality rates. Despite advances in conventional treatment modalities, patients with metastatic CRC often face limited options and poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy, initially successful in hematologic malignancies, presents a promising avenue for treating solid tumors, including CRC. This review explores the potential of CAR-T cell therapy in CRC by analyzing clinical trials and highlighting prominent CRC-specific targets. We discuss the challenges such as immunosuppressive microenvironment, tumor heterogeneity, and physical barriers that limit CAR-T efficacy. Emerging strategies, such as logic-gated and dual-targeting CAR-T cells, offer practical solutions to overcome these hurdles. Furthermore, we explore the combination of CAR-T cell therapy with immune checkpoint inhibitors to enhance T-cell persistence and tumor infiltration. As the field continues to evolve, CAR-T cell therapies hold significant potential for revolutionizing the treatment landscape of CRC.
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Affiliation(s)
- Shaida Ouladan
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Elias Orouji
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Gila F, Khoddam S, Jamali Z, Ghasemian M, Shakeri S, Dehghan Z, Fallahi J. Personalized medicine in colorectal cancer: a comprehensive study of precision diagnosis and treatment. Per Med 2025; 22:59-81. [PMID: 39924822 DOI: 10.1080/17410541.2025.2459050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
Colorectal cancer is a common and fatal disease that affects many people globally. CRC is classified as the third most prevalent cancer among males and the second most frequent cancer among females worldwide. The purpose of this article is to examine how personalized medicine might be used to treat colorectal cancer. The classification of colorectal cancer based on molecular profiling, including the detection of significant gene mutations, genomic instability, and gene dysregulation, is the main topic of this discussion. Advanced technologies and biomarkers are among the detection methods that are explored, demonstrating their potential for early diagnosis and precise prognosis. In addition, the essay explores the world of treatment possibilities by providing light on FDA-approved personalized medicine solutions that provide individualized and precise interventions based on patient characteristics. This article assesses targeted treatments like cetuximab and nivolumab, looks at the therapeutic usefulness of biomarkers like microsatellite instability (MSI) and circulating tumor DNA (ctDNA), and investigates new approaches to combat resistance. Through this, our review provides a thorough overview of personalized medicine in the context of colorectal cancer, ultimately highlighting its potential to revolutionize the field and improve patient care.
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Affiliation(s)
- Fatemeh Gila
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Khoddam
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Jamali
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohmmad Ghasemian
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shayan Shakeri
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Dehghan
- Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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Orhan A, Justesen TF, Raskov H, Qvortrup C, Gögenur I. Introducing Neoadjuvant Immunotherapy for Colorectal Cancer: Advancing the Frontier. Ann Surg 2025; 281:95-104. [PMID: 39005208 DOI: 10.1097/sla.0000000000006443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
OBJECTIVE To give surgeons a review of the current and future use of neoadjuvant immunotherapy in patients with localized colorectal cancer (CRC). BACKGROUND Immunotherapy has revolutionized the standard of care in oncology and improved survival outcomes in several cancers. However, the applicability of immunotherapy is still an ongoing challenge. Some cancer types are less responsive to immunotherapy, and the heterogeneity in responses within cancer types is poorly understood. Clinical characteristics of the patient, the timing of immunotherapy in relation to surgery, diversities in the immune responses, clonal heterogeneity, different features of the tumor microenvironment, and genetic alterations are some factors among many that may influence the efficacy of immunotherapy. RESULTS In this narrative review, we describe the major types of immunotherapy used to treat localized CRC. Furthermore, we discuss the prediction of response to immunotherapy in relation to biomarkers and radiologic assessment. Finally, we consider the future perspectives of clinical implications and response patterns, as well as the potential and challenges of neoadjuvant immunotherapy in localized CRC. CONCLUSIONS Establishing mismatch repair (MMR) status at the time of diagnosis is central to the potential use of neoadjuvant immunotherapy, in particular immune checkpoint inhibitors, in localized CRC. To date, efficacy is primarily seen in patients with deficient MMR status and polymerase epsilon mutations, although a small group of patients with proficient MMR does respond. In conclusion, neoadjuvant immunotherapy shows promising complete response rates, which may open a future avenue of an organ-sparing watch-and-wait approach for a group of patients.
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Affiliation(s)
- Adile Orhan
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Køge, Denmark
| | - Tobias F Justesen
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Køge, Denmark
| | - Hans Raskov
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Køge, Denmark
| | - Camilla Qvortrup
- Department of Clinical Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Ismail Gögenur
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Køge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Kaviyarasan V, Das A, Deka D, Saha B, Banerjee A, Sharma NR, Duttaroy AK, Pathak S. Advancements in immunotherapy for colorectal cancer treatment: a comprehensive review of strategies, challenges, and future prospective. Int J Colorectal Dis 2024; 40:1. [PMID: 39731596 DOI: 10.1007/s00384-024-04790-w] [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] [Accepted: 12/15/2024] [Indexed: 12/30/2024]
Abstract
PURPOSE Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Metastatic colorectal cancer (mCRC) continues to present significant challenges, particularly in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors. This narrative review aims to provide recent developments in immunotherapy for CRC treatment, focusing on its efficacy and challenges. METHODS This review discussed the various immunotherapeutic strategies for CRC treatment, including immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, combination therapies involving ICIs with other modalities, chimeric antigen receptor T-cell (CAR-T) cell therapy, and cancer vaccines. The role of the tumor microenvironment and immune evasion mechanisms was also explored to understand their impact on the effectiveness of these therapies. RESULTS This review provides a comprehensive update of recent advancements in immunotherapy for CRC, highlighting the potential of various immunotherapeutic approaches, including immune checkpoint inhibitors, combination therapies, CAR-T therapy, and vaccination strategies. The results of checkpoint inhibitors, particularly in patients with MSI-H/dMMR tumors, which have significant improvements in survival rates have been observed. Furthermore, this review also addresses the challenges faced in treating pMMR/MSS CRC, which remains resistant to immunotherapy. CONCLUSION Immunotherapy plays a significant role in the treatment of CRC, particularly in patients with MSI-H/dMMR tumors. However, many challenges remain, especially in treating pMMR/MSS CRC. This review discussed the need for further research into combination therapies, biomarker development, CAR-T cell therapy, and a deeper understanding of immune evasion mechanisms for CRC treatment.
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Affiliation(s)
- Vaishak Kaviyarasan
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Dikshita Deka
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Biki Saha
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India.
| | - Neeta Raj Sharma
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, Tamil Nadu, 603103, India.
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Duta-Ion SG, Juganaru IR, Hotinceanu IA, Dan A, Burtavel LM, Coman MC, Focsa IO, Zaruha AG, Codreanu PC, Bohiltea LC, Radoi VE. Redefining Therapeutic Approaches in Colorectal Cancer: Targeting Molecular Pathways and Overcoming Resistance. Int J Mol Sci 2024; 25:12507. [PMID: 39684219 DOI: 10.3390/ijms252312507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. This review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.
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Affiliation(s)
- Simona Gabriela Duta-Ion
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ioana Ruxandra Juganaru
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Iulian Andrei Hotinceanu
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Andra Dan
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Livia Malina Burtavel
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Madalin Codrut Coman
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ina Ofelia Focsa
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Andra Giorgiana Zaruha
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Patricia Christina Codreanu
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Laurentiu Camil Bohiltea
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- "Alessandrescu-Rusescu" National Institute for Maternal and Child Health, 20382 Bucharest, Romania
| | - Viorica Elena Radoi
- Department of Medical Genetics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- "Alessandrescu-Rusescu" National Institute for Maternal and Child Health, 20382 Bucharest, Romania
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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: 54] [Impact Index Per Article: 54.0] [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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11
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Yu B, Kang J, Lei H, Li Z, Yang H, Zhang M. Immunotherapy for colorectal cancer. Front Immunol 2024; 15:1433315. [PMID: 39238638 PMCID: PMC11375682 DOI: 10.3389/fimmu.2024.1433315] [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: 05/16/2024] [Accepted: 07/30/2024] [Indexed: 09/07/2024] Open
Abstract
Colorectal cancer is the third most common cancer and the second most lethal cancer in the world. The main cause of the disease is due to dietary and behavioral factors. The treatment of this complex disease is mainly based on traditional treatments, including surgery, radiotherapy, and chemotherapy. Due to its high prevalence and high morbidity, more effective treatments with fewer side effects are urgently needed. In recent years, immunotherapy has become a potential therapeutic alternative and one of the fastest-developing treatments. Immunotherapy inhibits tumor growth by activating or enhancing the immune system to recognize and attack cancer cells. This review presents the latest immunotherapies for immune checkpoint inhibitors, cell therapy, tumor-infiltrating lymphocytes, and oncolytic viruses. Some of these have shown promising results in clinical trials and are used in clinical treatment.
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Affiliation(s)
- Bing Yu
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
| | - Jian Kang
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
| | - Hong Lei
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
| | - Zhe Li
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
| | - Hao Yang
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
| | - Meng Zhang
- Department of the Colorectal Anal Surgery, The Affiliated Taian City Centeral Hospital of Qingdao University, Tai'an, Shandong, China
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12
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Fan S, Zhang W, Zhou L, Wang D, Tang D. Potential role of the intratumoral microbiota in colorectal cancer immunotherapy. Int Immunopharmacol 2024; 137:112537. [PMID: 38909493 DOI: 10.1016/j.intimp.2024.112537] [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: 04/21/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Colorectal cancer (CRC) has been one of the most common malignancies worldwide. Despite the advances in current therapies, the mortality rate of CRC remains high. Among them, immunotherapy has achieved satisfactory results in some CRC patients, however, how to expand the use of immunotherapy in CRC patients remains an urgent challenge. Surprisingly, the intratumoral microbiota has been found in multiple tumor tissues, including CRC. It has been demonstrated that the intratumoral microbiota is associated with the progression and treatment of CRC, and is able to enhance or decrease anti-tumor immune responses via different mechanisms as well as influence the immunotherapy efficacy, providing new potential therapeutic targets for CRC immunotherapy. In this review, we focus on the characteristics of the intratumoral microbiota, its roles in the genesis and development of CRC, its modulation of anti-tumor immune responses and immunotherapy, and propose potential applications of the intratumoral microbiota in CRC immunotherapy. Additionally, we propose possible directions for future research on the intratumoral microbiota related to CRC immunotherapy.
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Affiliation(s)
- Shiying Fan
- Clinical Medical College, Yangzhou University, Yangzhou 225000, PR China.
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing 400030, PR China.
| | - Lujia Zhou
- Clinical Medical College, Yangzhou University, Yangzhou 225000, PR China.
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225000, PR China.
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225000, PR China.
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13
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Nie SC, Jing YH, Lu L, Ren SS, Ji G, Xu HC. Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies. World J Gastrointest Oncol 2024; 16:1690-1704. [PMID: 38764816 PMCID: PMC11099432 DOI: 10.4251/wjgo.v16.i5.1690] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/30/2024] [Accepted: 03/11/2024] [Indexed: 05/09/2024] Open
Abstract
Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.
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Affiliation(s)
- Shu-Chang Nie
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Hua Jing
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China
| | - Si-Si Ren
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine), Shanghai 200032, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine), Shanghai 200032, China
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14
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Kita K, Burdowski A. Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management. World J Gastroenterol 2024; 30:1780-1790. [PMID: 38659489 PMCID: PMC11036503 DOI: 10.3748/wjg.v30.i13.1780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/08/2024] [Accepted: 03/19/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) has remained the second and the third leading cause of cancer-related death worldwide and in the United States, respectively. Although significant improvement in overall survival has been achieved, death in adult populations under the age of 55 appears to have increased in the past decades. Although new classes of therapeutic strategies such as immunotherapy have emerged, their application is very limited in CRC so far. Microtubule (MT) inhibitors such as taxanes, are not generally successful in CRC. There may be some way to make MT inhibitors work effectively in CRC. One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices. A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs. In this Editorial review, we would like to discuss the potential of optogenetic approaches in CRC management.
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Affiliation(s)
- Katsuhiro Kita
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
| | - Allen Burdowski
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
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15
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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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16
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Liu Y, Peng C, Ahad F, Ali Zaidi SA, Muluh TA, Fu Q. Advanced Strategies of CAR-T Cell Therapy in Solid Tumors and Hematological Malignancies. Recent Pat Anticancer Drug Discov 2024; 19:557-572. [PMID: 38213150 DOI: 10.2174/0115748928277331231218115402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/30/2023] [Accepted: 11/10/2023] [Indexed: 01/13/2024]
Abstract
Chimeric antigen receptor T-cells, known as CAR-T cells, represent a promising breakthrough in the realm of adoptive cell therapy. These T-cells are genetically engineered to carry chimeric antigen receptors that specifically target tumors. They have achieved notable success in the treatment of blood-related cancers, breathing new life into this field of medical research. However, numerous obstacles limit chimeric antigen receptors T-cell therapy's efficacy, such as it cannot survive in the body long. It is prone to fatigue and exhaustion, leading to difficult tumor elimination and repeated recurrence, affecting solid tumors and hematological malignancies. The challenges posed by solid tumors, especially in the context of the complex solid-tumor microenvironment, require specific strategies. This review outlines recent advancements in improving chimeric antigen receptors T-cell therapy by focusing on the chimeric antigen receptors protein, modifying T-cells, and optimizing the interaction between T-cells and other components within the tumor microenvironment. This article aims to provide an extensive summary of the latest discoveries regarding CAR-T cell therapy, encompassing its application across various types of human cancers. Moreover, it will delve into the obstacles that have emerged in recent times, offering insights into the challenges faced by this innovative approach. Finally, it highlights novel therapeutic options in treating hematological and solid malignancies with chimeric antigen receptors T-cell therapies.
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Affiliation(s)
- Yangjie Liu
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan, PRC China
| | - Cao Peng
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan PRC China
| | - Faiza Ahad
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Syed Aqib Ali Zaidi
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Tobias Achu Muluh
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Qiuxia Fu
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan PRC China
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17
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Zhang H, Zhu M, Zhao A, Shi T, Xi Q. B7-H3 regulates anti-tumor immunity and promotes tumor development in colorectal cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189031. [PMID: 38036107 DOI: 10.1016/j.bbcan.2023.189031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract and one of the most common causes of cancer-related deaths worldwide. Immune checkpoint inhibitors have become a milestone in many cancer treatments with significant curative effects. However, its therapeutic effect on colorectal cancer is still limited. B7-H3 is a novel immune checkpoint molecule of the B7/CD28 family and is overexpressed in a variety of solid tumors including colorectal cancer. B7-H3 was considered as a costimulatory molecule that promotes anti-tumor immunity. However, more and more studies support that B7-H3 is a co-inhibitory molecule and plays an important immunosuppressive role in colorectal cancer. Meanwhile, B7-H3 promoted metabolic reprogramming, invasion and metastasis, and chemoresistance in colorectal cancer. Therapies targeting B7-H3, including monoclonal antibodies, antibody drug conjugations, and chimeric antigen receptor T cells, have great potential to improve the prognosis of colorectal cancer patients.
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Affiliation(s)
- Huan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mengxin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Anjing Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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18
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Cao Y, Efetov SK, He M, Fu Y, Beeraka NM, Zhang J, Zhang X, Bannimath N, Chen K. Updated Clinical Perspectives and Challenges of Chimeric Antigen Receptor-T Cell Therapy in Colorectal Cancer and Invasive Breast Cancer. Arch Immunol Ther Exp (Warsz) 2023; 71:19. [DOI: https:/doi.org/10.1007/s00005-023-00684-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/28/2023] [Indexed: 09/20/2024]
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19
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Zhu S, Cheng Y, Wang J, Liu G, Luo T, Li X, Yang S, Yang R. Biohybrid magnetic microrobots: An intriguing and promising platform in biomedicine. Acta Biomater 2023; 169:88-106. [PMID: 37572981 DOI: 10.1016/j.actbio.2023.08.005] [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: 05/30/2023] [Revised: 07/19/2023] [Accepted: 08/03/2023] [Indexed: 08/14/2023]
Abstract
Biohybrid magnetic microrobots (BMMs) have emerged as an exciting class of microrobots and have been considered as a promising platform in biomedicine. Many microorganisms and body's own cells show intriguing properties, such as morphological characteristics, biosafety, and taxis abilities (e.g., chemotaxis, aerotaxis), which have made them attractive for the fabrication of microrobots. For remote controllability and sustainable actuation, magnetic components are usually incorporated onto these biological entities, and other functionalized non-biological components (e.g., therapeutic agents) are also included for specific applications. This review highlights the latest developments in BMMs with a focus on their biomedical applications. It starts by introducing the fundamental understanding of the propulsion system at the microscale in a magnetically driven manner, followed by a summary of diverse BMMs based on different microorganisms and body's own cells along with their relevant applications. Finally, the review discusses how BMMs contribute to the advancements of microrobots, the current challenges of using BMMs in practical clinical settings, and the future perspectives of this exciting field. STATEMENT OF SIGNIFICANCE: Biohybrid magnetic microrobots (BMMs), composed of biological entities and functional parts, hold great potential and serve as a novel and promising platform for biomedical applications such as targeted drug delivery. This review comprehensively summarizes the recent advancements in BMMs for biomedical applications, mainly focused on the representative propulsion modalities in a magnetically propelled manner and diverse designs of BMMs based on different biological entities, including microorganisms and body's own cells. We hope this review can provide ideas for the future design, development, and innovation of micro/nanorobots in the field of biomedicine.
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Affiliation(s)
- Shilu Zhu
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Yifan Cheng
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Jian Wang
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Guangli Liu
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Tingting Luo
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China.
| | - Xiaojian Li
- Department of Management, Hefei University of Technology, Hefei 230009, China.
| | - Shanlin Yang
- Key Laboratory of Process Optimization and Intelligent Decision-Making (Ministry of Education), Hefei University of Technology, Hefei 230009, China.
| | - Runhuai Yang
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China.
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20
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Cao Y, Efetov SK, He M, Fu Y, Beeraka NM, Zhang J, Zhang X, Bannimath N, Chen K. Updated Clinical Perspectives and Challenges of Chimeric Antigen Receptor-T Cell Therapy in Colorectal Cancer and Invasive Breast Cancer. Arch Immunol Ther Exp (Warsz) 2023; 71:19. [PMID: 37566162 DOI: 10.1007/s00005-023-00684-x] [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: 02/25/2023] [Accepted: 06/28/2023] [Indexed: 08/12/2023]
Abstract
In recent years, the incidence of colorectal cancer (CRC) and breast cancer (BC) has increased worldwide and caused a higher mortality rate due to the lack of selective anti-tumor therapies. Current chemotherapies and surgical interventions are significantly preferred modalities to treat CRC or BC in advanced stages but the prognosis for patients with advanced CRC and BC remains dismal. The immunotherapy technique of chimeric antigen receptor (CAR)-T cells has resulted in significant clinical outcomes when treating hematologic malignancies. The novel CAR-T therapy target antigens include GUCY2C, CLEC14A, CD26, TEM8/ANTXR1, PDPN, PTK7, PODXL, CD44, CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D. The significant aim of this review is to explore the recently updated information pertinent to several novel targets of CAR-T for CRC, and BC. We vividly described the challenges of CAR-T therapies when treating CRC or BC. The immunosuppressive microenvironment of solid tumors, the shortage of tumor-specific antigens, and post-treatment side effects are the major hindrances to promoting the development of CAR-T cells. Several clinical trials related to CAR-T immunotherapy against CRC or BC have already been in progress. This review benefits academicians, clinicians, and clinical oncologists to explore more about the novel CAR-T targets and overcome the challenges during this therapy.
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Affiliation(s)
- Yu Cao
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Sergey K Efetov
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Mingze He
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Yu Fu
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Narasimha M Beeraka
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu, Anantapuramu, Andhra Pradesh, 515721, India
| | - Jin Zhang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Xinliang Zhang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Namitha Bannimath
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, Karnataka, India
| | - Kuo Chen
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, #1 Jianshedong Str., Zhengzhou, 450052, People's Republic of China.
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21
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Chelakkot C, Chelakkot VS, Shin Y, Song K. Modulating Glycolysis to Improve Cancer Therapy. Int J Mol Sci 2023; 24:2606. [PMID: 36768924 PMCID: PMC9916680 DOI: 10.3390/ijms24032606] [Citation(s) in RCA: 148] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
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Affiliation(s)
| | - Vipin Shankar Chelakkot
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Youngkee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung Song
- College of Pharmacy, Duksung Women’s University, Seoul 01366, Republic of Korea
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