|
1
|
Tian HP, Xiao ZX, Su BW, Li YX, Peng H, Meng CY. Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights. World J Gastrointest Oncol 2025; 17:99188. [DOI: 10.4251/wjgo.v17.i4.99188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/08/2024] [Accepted: 01/15/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND SLC16A8, a lactate efflux transporter, is upregulated in various cancers, but its effects on tumor microenvironments remain understudied. This research explores its role in colorectal cancer (CRC) and the impact on the associated microenvironment consisting of vascular endothelial cells.
AIM To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.
METHODS Hypoxic conditions prompted examination of SLC16A8 expression, glycolysis, lactate efflux, and Warburg effect correlations in CRC cell lines. Co-culture with HUVEC allowed for endothelial-mesenchymal transition (EndMT) characterization, revealing lactate efflux's influence. Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments, investigating tumor growth, blood vessel distribution, and signaling pathway alterations.
RESULTS SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression (P < 0.05). Under hypoxic conditions, HIF-1α induced SLC16A8 expression, leading to enhanced metabolic reprogramming and increased lactate production. siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes, including reduced glucose consumption and lactate production. Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells. In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth, reduced Ki67 expression, and decreased HIF-1α levels. Furthermore, SLC16A8 silencing led to decreased expression of key metabolic enzymes PKM2 and LDHA, indicating its role in glycolytic regulation.
CONCLUSION Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.
Collapse
Affiliation(s)
- Hong-Peng Tian
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zhong-Xiang Xiao
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Bo-Wen Su
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yi-Xuan Li
- Department of Premarital and Prenatal Examination, Nanchong Shunqing District Maternal and Child Health Hospital, Nanchong 637000, Sichuan Province, China
| | - Hong Peng
- Department of Anorectal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Chang-Yuan Meng
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| |
Collapse
|
|
2
|
Jamal A, Aldreiwish AD, Banawas SS, Alqurashi YE, Kamal MA, Ahmad F. The paths toward immunotherapy of esophageal cancer: An overview of clinical trials. Int Immunopharmacol 2025; 151:114261. [PMID: 40015204 DOI: 10.1016/j.intimp.2025.114261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/26/2025] [Accepted: 02/06/2025] [Indexed: 03/01/2025]
Abstract
As the seventh-leading contributor to global cancer-related deaths, esophageal cancer (EC) is one of the most challenging types of cancer. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the five-year survival rate remains low, underscoring the need for the development of more efficacious treatment approaches. Immunotherapy has emerged as a promising treatment approach, offering new hope for EC patients. This review provides an in-depth examination of the latest immunotherapeutic strategies for EC, focusing on immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and oncolytic virotherapy. We critically analyze the current clinical data to highlight the progress and pitfalls of each immunotherapeutic approach for EC. Additionally, we explore the potential for combination therapies, which could overcome the resistance often seen with monotherapies. Finally, we discuss the limitations of current treatments and outline key areas for future research to improve patient outcomes and survival.
Collapse
Affiliation(s)
- Azfar Jamal
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia; Health and Basic Science Research Centre, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - Allolo D Aldreiwish
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Saeed S Banawas
- Health and Basic Science Research Centre, Majmaah University, Al-Majmaah 11952, Saudi Arabia; Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Yaser E Alqurashi
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Fuzail Ahmad
- Respiratory Care Department, College of Applied Sciences, Almaarefa University, Diriya, Riyadh 13713, Saudi Arabia
| |
Collapse
|
|
3
|
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.
Collapse
Affiliation(s)
- Shaida Ouladan
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Elias Orouji
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
4
|
Gerber WK, Xie Y, Patel SA. Expanding the Therapeutic Reach of Chimeric Antigen Receptor T-Cells and Bispecific T-Cell Engagers Across Solid Tumors. JCO Precis Oncol 2025; 9:e2400753. [PMID: 40138603 PMCID: PMC11952672 DOI: 10.1200/po-24-00753] [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: 10/17/2024] [Revised: 01/29/2025] [Accepted: 02/06/2025] [Indexed: 03/29/2025] Open
Abstract
The introduction of T-cell-based therapeutics in hematologic malignancies has led to improvements in outcomes for patients with acute leukemia, lymphoma, and multiple myeloma. To date, the Food and Drug Administration (FDA) has approved seven chimeric antigen receptor-T (CAR-T) cell therapies and seven bispecific T-cell engagers (BiTEs) across a variety of hematologic malignancies; however, the extension of CAR-T therapies and BiTEs to the solid tumor arena has been somewhat limited. In this review, we discuss the landmark data that led to the commercialization of four novel FDA-approved T-cell-based therapeutics in solid malignancies, including tarlatamab for small cell lung cancer, afamitresgene autoleucel for synovial sarcoma, lifileucel for metastatic melanoma, and tebentafusp for metastatic uveal melanoma. We discuss the targetable antigen landscape of CAR-T therapies and BiTEs under investigation in solid malignancies. We explore the translational potential for various CARs under active investigation, including human epidermal growth factor receptor 2-directed CARs in breast cancer, prostate stem cell antigen-directed CARs for prostate cancer, epidermal growth factor receptor (EGFR)-IL13Ra2 and EGFR-vIII CARs for glioblastoma, and GD2-directed CARs for neuroblastoma. We glean from lessons learned for existing CAR-T therapies and BiTEs for hematologic malignancies and emphasize solutions toward facilitating the clinical rollout of T-cell-based therapies in solid tumors, including scalability to meet the growing needs of clinical oncology. Some solutions include addressing on-target, off-tumor toxicity; improving the manufacturing of CARs; optimizing the tissue-specific tumor microenvironment by combating immune desert tumors; and discovering natural tumor neoantigens and non-self-epitopes generated by tumor-specific mutations. These concepts can help provide transformative benefits for patients with solid malignancies in the coming years.
Collapse
Affiliation(s)
- William K. Gerber
- Dept. of Medicine – Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA
| | - Yiyu Xie
- Dept. of Medicine – Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA
| | - Shyam A. Patel
- Dept. of Medicine – Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA
- Center for Clinical and Translational Science, UMass Chan Medical School, Worcester, MA
- Cancer Biology Program, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA
| |
Collapse
|
|
5
|
Jin Z, Li Y, Yi H, Wang M, Wang C, Du S, Zeng W, Zong Z. Pathogenetic development, diagnosis and clinical therapeutic approaches for liver metastasis from colorectal cancer (Review). Int J Oncol 2025; 66:22. [PMID: 39950314 PMCID: PMC11844340 DOI: 10.3892/ijo.2025.5728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 01/10/2025] [Indexed: 02/23/2025] Open
Abstract
Colorectal cancer (CRC) is a prevalent malignancy and a significant proportion of patients with CRC develop liver metastasis (CRLM), which is a major contributor to CRC‑related mortality. The present review aimed to comprehensively examine the pathogenetic development and diagnosis of CRLM and the clinical therapeutic approaches for treatment of this disease. The molecular mechanisms underlying CRLM were discussed, including the role of the tumour microenvironment and epithelial‑mesenchymal transition. The present review also highlighted the importance of early detection and the current challenges in predicting the development of CRLM. Various treatment strategies were reviewed, including surgical resection, chemotherapy and immunotherapy, and the potential of novel therapies, such as selective internal radiation therapy and Traditional Chinese Medicine. Despite recent advancements in treatment options, the treatment of CRLM remains a therapeutic challenge due to the complexity of the liver microenvironment and the heterogeneity of CRC. The present review emphasized the need for a multidisciplinary approach and the integration of emerging therapies to improve patient outcomes.
Collapse
Affiliation(s)
- Zhenhua Jin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yin Li
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hao Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Menghui Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chaofeng Wang
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shaokun Du
- The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wenjuan Zeng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| |
Collapse
|
|
6
|
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.
Collapse
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.
| |
Collapse
|
|
7
|
Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [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: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
Collapse
Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| |
Collapse
|
|
8
|
Venturini J, Massaro G, Lavacchi D, Rossini D, Pillozzi S, Caliman E, Pellegrini E, Antonuzzo L. The emerging HER2 landscape in colorectal cancer: the key to unveil the future treatment algorithm? Crit Rev Oncol Hematol 2024; 204:104515. [PMID: 39304034 DOI: 10.1016/j.critrevonc.2024.104515] [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: 02/02/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
Abstract
Colorectal cancer (CRC) represents a global health threat, standing as the second leading cause of cancer-related death worldwide. Targeted therapies brought new hope for the metastatic stage, which historically bore a very poor prognosis. Human epidermal growth receptor 2 (HER2) overexpression concerns about 5 % of the metastatic CRC (mCRC) patients, including both gene amplifications and point mutations. Albeit its controversial prognostic role, preclinical and clinical data indicate HER2 as a negative predictive biomarker of response to anti-EGFR therapies. Tissue and plasma-based NGS testing, could permit a precise identification of this resistance mechanism both at baseline and during treatment, thus guiding decision-making. Furthermore, promising results come from completed and ongoing randomized trials, testing HER2 as an actionable target. In this review, we discuss the available evidence on HER2 targeting in advanced CRC, analyzing its possible future role in the treatment algorithm.
Collapse
Affiliation(s)
- Jacopo Venturini
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Giulia Massaro
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Daniele Lavacchi
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Daniele Rossini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Department of Health Science, University of Florence, Florence 50139, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Enrico Caliman
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Elisa Pellegrini
- Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy.
| |
Collapse
|
|
9
|
Khaliulin M, Valiullina A, Petukhov A, Yuan Y, Spada S, Bulatov E. Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells. Cancer Immunol Immunother 2024; 74:3. [PMID: 39487875 PMCID: PMC11531461 DOI: 10.1007/s00262-024-03817-z] [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: 03/30/2024] [Accepted: 08/22/2024] [Indexed: 11/04/2024]
Abstract
The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.
Collapse
Affiliation(s)
- Marat Khaliulin
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 420008
| | - Aygul Valiullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 420008
| | - Alexey Petukhov
- Nazarbaev University, Qabanbay Batyr Ave 53, 010000, Astana, Kazakhstan
| | - Youyong Yuan
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, People's Republic of China
| | - Sheila Spada
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy
| | - Emil Bulatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 420008.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia, 117997.
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia, 119048.
| |
Collapse
|
|
10
|
Li W, Huang Y, Zhou X, Cheng B, Wang H, Wang Y. CAR-T therapy for gastrointestinal cancers: current status, challenges, and future directions. Braz J Med Biol Res 2024; 57:e13640. [PMID: 39417449 PMCID: PMC11484376 DOI: 10.1590/1414-431x2024e13640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 07/26/2024] [Indexed: 10/19/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary immunotherapeutic strategy that has shown efficacy in hematological malignancies. However, its application in solid tumors, particularly gastrointestinal cancers, faces significant challenges. These include the selection of target antigens, the complexity of the tumor microenvironment, and safety and toxicity concerns. This review provides a current overview of CAR-T therapy in various gastrointestinal cancers, such as esophageal, gastric, colorectal, pancreatic, and liver cancers. It discusses the limitations and future directions of CAR-T therapy in this context. This review highlights innovative strategies, including novel target antigens, multispecific CAR-T cells, armored CAR-T cells, and the development of universal CAR-T cells. These insights aim to inform ongoing research and foster advancements in CAR-T therapy for gastrointestinal cancers.
Collapse
Affiliation(s)
- Weidong Li
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Yueming Huang
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Xinhao Zhou
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Bohao Cheng
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Haitao Wang
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Yao Wang
- Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| |
Collapse
|
|
11
|
Zhang R, Su C, Jia Y, Xing M, Jin S, Zong H. Molecular mechanisms of HER2-targeted therapy and strategies to overcome the drug resistance in colorectal cancer. Biomed Pharmacother 2024; 179:117363. [PMID: 39236476 DOI: 10.1016/j.biopha.2024.117363] [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: 06/11/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
HER2 amplification is one of the mechanisms that induce drug resistance to anti-EGFR therapy in colorectal cancer. In recent years, data from several randomized clinical trials show that anti-HER2 therapies improved the prognosis of patients with HER2-positive colorectal cancer. These results indicate that HER2 is a promising therapeutic target in advanced colorectal cancer. Despite the anti-HER2 therapies including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates improving the outcomes, less than 30 % of the patients achieve objective response and eventually have drug resistance. It is necessary to explore the primary and secondary mechanisms for the resistance to anti-HER2 therapies, which will pave the way to overcome the drug resistance. Several studies have reported the potential mechanisms for the resistance to anti-HER2 therapies. In this review, we present a comprehensive overview of the recent advances in clinical research, mechanisms of treatment resistance, and strategies for reversing resistance in HER2-positive colorectal cancer patients.
Collapse
Affiliation(s)
- Rui Zhang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Chang Su
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Yongliang Jia
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - Menglu Xing
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Shuiling Jin
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Hong Zong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| |
Collapse
|
|
12
|
Shalaby N, Xia Y, Kelly JJ, Sanchez-Pupo R, Martinez F, Fox MS, Thiessen JD, Hicks JW, Scholl TJ, Ronald JA. Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography. Eur J Nucl Med Mol Imaging 2024; 51:3176-3190. [PMID: 38722382 PMCID: PMC11368970 DOI: 10.1007/s00259-024-06722-w] [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: 02/20/2024] [Accepted: 04/14/2024] [Indexed: 09/03/2024]
Abstract
Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.
Collapse
Affiliation(s)
- Nourhan Shalaby
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
| | - Ying Xia
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - John J Kelly
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Rafael Sanchez-Pupo
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Francisco Martinez
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Matthew S Fox
- Lawson Health Research Institute, London, ON, Canada
- Saint Joseph's Health Care, London, ON, Canada
| | - Jonathan D Thiessen
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Lawson Cyclotron and Radiochemistry Facility, London, ON, Canada
- Saint Joseph's Health Care, London, ON, Canada
| | - Justin W Hicks
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Lawson Health Research Institute, London, ON, Canada
- Lawson Cyclotron and Radiochemistry Facility, London, ON, Canada
| | - Timothy J Scholl
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Ontario Institute for Cancer Research, London, ON, Canada
| | - John A Ronald
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Lawson Health Research Institute, London, ON, Canada
| |
Collapse
|
|
13
|
Chen T, Ma W, Wang X, Ye Q, Hou X, Wang Y, Jiang C, Meng X, Sun Y, Cai J. Insights of immune cell heterogeneity, tumor-initiated subtype transformation, drug resistance, treatment and detecting technologies in glioma microenvironment. J Adv Res 2024:S2090-1232(24)00315-1. [PMID: 39097088 DOI: 10.1016/j.jare.2024.07.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/30/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024] Open
Abstract
BACKGROUND With the gradual understanding of glioma development and the immune microenvironment, many immune cells have been discovered. Despite the growing comprehension of immune cell functions and the clinical application of immunotherapy, the precise roles and characteristics of immune cell subtypes, how glioma induces subtype transformation of immune cells and its impact on glioma progression have yet to be understood. AIM OF THE REVIEW In this review, we comprehensively center on the four major immune cells within the glioma microenvironment, particularly neutrophils, macrophages, lymphocytes, myeloid-derived suppressor cells (MDSCs), and other significant immune cells. We discuss (1) immune cell subtype markers, (2) glioma-induced immune cell subtype transformation, (3) the mechanisms of each subtype influencing chemotherapy resistance, (4) therapies targeting immune cells, and (5) immune cell-associated single-cell sequencing. Eventually, we identified the characteristics of immune cell subtypes in glioma, comprehensively summarized the exact mechanism of glioma-induced immune cell subtype transformation, and concluded the progress of single-cell sequencing in exploring immune cell subtypes in glioma. KEY SCIENTIFIC CONCEPTS OF REVIEW In conclusion, we have analyzed the mechanism of chemotherapy resistance detailly, and have discovered prospective immunotherapy targets, excavating the potential of novel immunotherapies approach that synergistically combines radiotherapy, chemotherapy, and surgery, thereby paving the way for improved immunotherapeutic strategies against glioma and enhanced patient outcomes.
Collapse
Affiliation(s)
- Tongzheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenbin Ma
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qile Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xintong Hou
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yiwei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chuanlu Jiang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Six Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangqi Meng
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Ying Sun
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Jinquan Cai
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| |
Collapse
|
|
14
|
Singh M, Morris VK, Bandey IN, Hong DS, Kopetz S. Advancements in combining targeted therapy and immunotherapy for colorectal cancer. Trends Cancer 2024; 10:598-609. [PMID: 38821852 DOI: 10.1016/j.trecan.2024.05.001] [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: 01/11/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 06/02/2024]
Abstract
Colorectal cancer (CRC) is a prevalent gastrointestinal cancer posing significant clinical challenges. CRC management traditionally involves surgery, often coupled with chemotherapy. However, unresectable or metastatic CRC (mCRC) presents a complex challenge necessitating innovative treatment strategies. Targeted therapies have emerged as the cornerstone of treatment in such cases, with interventions tailored to specific molecular attributes. Concurrently, immunotherapies have revolutionized cancer treatment by harnessing the immune system to combat malignant cells. This review explores the evolving landscape of CRC treatment, focusing on the synergy between immunotherapies and targeted therapies, thereby offering new avenues for enhancing the effectiveness of therapy for CRC.
Collapse
Affiliation(s)
- Manisha Singh
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Van Karlyle Morris
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Irfan N Bandey
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David S Hong
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
15
|
Zheng E, Włodarczyk M, Węgiel A, Osielczak A, Możdżan M, Biskup L, Grochowska A, Wołyniak M, Gajewski D, Porc M, Maryńczak K, Dziki Ł. Navigating through novelties concerning mCRC treatment-the role of immunotherapy, chemotherapy, and targeted therapy in mCRC. Front Surg 2024; 11:1398289. [PMID: 38948479 PMCID: PMC11211389 DOI: 10.3389/fsurg.2024.1398289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/29/2024] [Indexed: 07/02/2024] Open
Abstract
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
Collapse
Affiliation(s)
- Edward Zheng
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marcin Włodarczyk
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Andrzej Węgiel
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Aleksandra Osielczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Możdżan
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Laura Biskup
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Agata Grochowska
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Wołyniak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Dominik Gajewski
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Mateusz Porc
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
16
|
Zhou G, Fu S, Zhang Y, Li S, Guo Z, Ouyang D, Ying T, Lu Y, Zhao Q. Antibody Recognition of Human Epidermal Growth Factor Receptor-2 (HER2) Juxtamembrane Domain Enhances Anti-Tumor Response of Chimeric Antigen Receptor (CAR)-T Cells. Antibodies (Basel) 2024; 13:45. [PMID: 38920969 PMCID: PMC11200690 DOI: 10.3390/antib13020045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy shows promise in treating malignant tumors. However, the use of human epidermal growth factor receptor-2 (HER2) CAR-T cells carries the risk of severe toxicity, including cytokine release syndrome, due to their "on-target off-tumor" recognition of HER2. Enhancing the quality and functionality of HER2 CARs could greatly improve the therapeutic potential of CAR-T cells. In this study, we developed a novel anti-HER2 monoclonal antibody, Ab8, which targets domain III of HER2, distinct from the domain IV recognition of trastuzumab. Although two anti-HER2 mAbs induced similar levels of antibody-dependent cellular cytotoxicity, trastuzumab-based CAR-T cells exhibited potent antitumor activity against HER2-positive cancer cells. In conclusion, our findings provide scientific evidence that antibody recognition of the membrane-proximal domain promotes the anti-tumor response of HER2-specific CAR-T cells.
Collapse
Affiliation(s)
- Guangyu Zhou
- Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau SAR, China; (G.Z.); (S.F.); (Z.G.)
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau SAR, China
| | - Shengyu Fu
- Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau SAR, China; (G.Z.); (S.F.); (Z.G.)
| | - Yunsen Zhang
- Institute of Chinese Medical Sciences, University of Macau, Taipa 999078, Macau SAR, China; (Y.Z.); (D.O.)
| | - Shuang Li
- The Fifth Medical Center of the PLA General Hospital, Beijing 100036, China;
| | - Ziang Guo
- Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau SAR, China; (G.Z.); (S.F.); (Z.G.)
| | - Defang Ouyang
- Institute of Chinese Medical Sciences, University of Macau, Taipa 999078, Macau SAR, China; (Y.Z.); (D.O.)
| | - Tianlei Ying
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;
| | - Yinying Lu
- The Fifth Medical Center of the PLA General Hospital, Beijing 100036, China;
| | - Qi Zhao
- Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau SAR, China; (G.Z.); (S.F.); (Z.G.)
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau SAR, China
| |
Collapse
|
|
17
|
Li X, Li W, Xu L, Song Y. Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments. Chin Med J (Engl) 2024; 137:1285-1302. [PMID: 37640679 PMCID: PMC11191032 DOI: 10.1097/cm9.0000000000002818] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Indexed: 08/31/2023] Open
Abstract
ABSTRACT The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an "off-the-shelf" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.
Collapse
Affiliation(s)
- Xudong Li
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Linping Xu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Yongping Song
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| |
Collapse
|
|
18
|
Moaveni AK, Amiri M, Shademan B, Farhadi A, Behroozi J, Nourazarian A. Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update. Front Mol Biosci 2024; 11:1382190. [PMID: 38836106 PMCID: PMC11149429 DOI: 10.3389/fmolb.2024.1382190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 03/27/2024] [Indexed: 06/06/2024] Open
Abstract
Pediatric cancers represent a tragic but also promising area for gene therapy. Although conventional treatments have improved survival rates, there is still a need for targeted and less toxic interventions. This article critically analyzes recent advances in gene therapy for pediatric malignancies and discusses the challenges that remain. We explore the innovative vectors and delivery systems that have emerged, such as adeno-associated viruses and non-viral platforms, which show promise in addressing the unique pathophysiology of pediatric tumors. Specifically, we examine the field of chimeric antigen receptor (CAR) T-cell therapies and their adaptation for solid tumors, which historically have been more challenging to treat than hematologic malignancies. We also discuss the genetic and epigenetic complexities inherent to pediatric cancers, such as tumor heterogeneity and the dynamic tumor microenvironment, which pose significant hurdles for gene therapy. Ethical considerations specific to pediatric populations, including consent and long-term follow-up, are also analyzed. Additionally, we scrutinize the translation of research from preclinical models that often fail to mimic pediatric cancer biology to the regulatory landscapes that can either support or hinder innovation. In summary, this article provides an up-to-date overview of gene therapy in pediatric oncology, highlighting both the rapid scientific progress and the substantial obstacles that need to be addressed. Through this lens, we propose a roadmap for future research that prioritizes the safety, efficacy, and complex ethical considerations involved in treating pediatric patients. Our ultimate goal is to move from incremental advancements to transformative therapies.
Collapse
Affiliation(s)
- Amir Kian Moaveni
- Pediatric Urology and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Amiri
- Pediatric Urology and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezoo Farhadi
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Javad Behroozi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| |
Collapse
|
|
19
|
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: 1] [Impact Index Per Article: 1.0] [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.
Collapse
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
| |
Collapse
|
|
20
|
Harrer DC, Li SS, Kaljanac M, Bezler V, Barden M, Pan H, Herr W, Abken H. Magnetic CAR T cell purification using an anti-G4S linker antibody. J Immunol Methods 2024; 528:113667. [PMID: 38574803 DOI: 10.1016/j.jim.2024.113667] [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: 01/09/2024] [Revised: 03/30/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
Chimeric antigen receptor (CAR) redirected T cells are successfully employed in the combat against several hematological malignancies, however, are often compromised by low transduction rates making refinement of the CAR T cell products necessary. Here, we report a broadly applicable enrichment protocol relying on marking CAR T cells with an anti-glycine4-serine (G4S) linker antibody followed by magnetic activated cell sorting (MACS). The protocol is broadly applicable since the G4S peptide is an integral part of the vast majority of CARs as it links the VH and VL recognition domains. We demonstrate the feasibility by using the canonical second generation CARs specific for CEA and Her2, respectively, obtaining highly purified CAR T cell products in a one-step procedure without impairing cell viability. The protocol is also applicable to a dual specific CAR (tandem CAR). Except for CD39, T cell activation/exhaustion markers were not upregulated after separation. Purified CAR T cells retained their functionality with respect to antigen-specific cytokine secretion, cytotoxicity, and the capacity to proliferate and eliminate cognate tumor cells upon repetitive stimulation. Collectively, the one-step protocol for purifying CAR T cells extends the toolbox for preclinical research and specifically for clinical CAR T cell manufacturing.
Collapse
Affiliation(s)
- Dennis Christoph Harrer
- Department of Internal Medicine III - Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany; Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany.
| | - Sin-Syue Li
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany; Division of Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Marcell Kaljanac
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany
| | - Valerie Bezler
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany
| | - Markus Barden
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany
| | - Hong Pan
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III - Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Hinrich Abken
- Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, and Chair Genetic Immunotherapy, University Regensburg, Germany
| |
Collapse
|
|
21
|
Robinson HR, Messersmith WA, Lentz RW. HER2-Positive Metastatic Colorectal Cancer. Curr Treat Options Oncol 2024; 25:585-604. [PMID: 38539034 DOI: 10.1007/s11864-024-01183-7] [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] [Accepted: 01/17/2024] [Indexed: 04/24/2024]
Abstract
OPINION STATEMENT Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.
Collapse
Affiliation(s)
- Hannah R Robinson
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA
| | - Wells A Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA
| | - Robert W Lentz
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA.
| |
Collapse
|
|
22
|
Chen T, Wang M, Chen Y, Liu Y. Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors. Cancer Cell Int 2024; 24:133. [PMID: 38622705 PMCID: PMC11017638 DOI: 10.1186/s12935-024-03315-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/26/2024] [Indexed: 04/17/2024] Open
Abstract
The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors.
Collapse
Affiliation(s)
- Tong Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Mingzhao Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yanchao Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yutao Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
| |
Collapse
|
|
23
|
Khaliulin MR, Safin RN, Kunst MA, Bulatov ER. The use of T-cells with chimeric antigen receptor (CAR-T) in combination with chemotherapy and radiotherapy for the treatment of solid tumors. ADVANCES IN MOLECULAR ONCOLOGY 2024; 11:31-45. [DOI: 10.17650/2313-805x-2024-11-1-31-45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The introduction of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological diseases, particularly in combating blood cancer. The success of this cell therapy approach has led to the development of approximately seven commercial CAR-T based drugs. However, the application of CAR-T therapy for solid tumors has proven to be less effective due to challenges such as the varied antigens in solid tumors, an immunosuppressive tumor environment, limited immune cell infiltration, reduced CAR-T cell activity and toxicity issues. To solve these problems, scientists are making efforts to improve and improve the methods of treatment of solid tumors. Chemotherapy is the standard treatment for a large number of malignant neoplasms. It is also used before starting cell therapy for lymphodepletion and better engraftment of injected CAR-T cells. It has been shown that chemotherapy can reduce the immunosuppressive effect of the tumor microenvironment, destroy the stroma, and promote better infiltration of the tumor by CAR-T cells, improving their survival, persistence, cytotoxicity, and influencing the metabolism of immune cells inside the tumor. The effectiveness of combining chemotherapy and CAR-T cell therapy relies on various factors such as tumor type, dosage, treatment schedule, CAR-T cell composition, and individual biological traits. Similarly, radiation therapy can enhance tumor cell vulnerability to specific treatments while also supporting tumor cell survival.In this review, we discuss the use of CAR-T therapy to combat solid tumors, regarding the challenges of treating solid tumors, ways to overcome them, and also touch upon the possibility of using combination treatments to improve the effectiveness of cell therapy.
Collapse
Affiliation(s)
| | - R. N. Safin
- Republican Clinical Oncology Dispensary named after Prof. M.Z. Sigal Russia
| | - M. A. Kunst
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - E. R. Bulatov
- Kazan (Volga Region) Federal University; Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences
| |
Collapse
|
|
24
|
Johnston AC, Alicea GM, Lee CC, Patel PV, Hanna EA, Vaz E, Forjaz A, Wan Z, Nair PR, Lim Y, Chen T, Du W, Kim D, Nichakawade TD, Rebecca VW, Bonifant CL, Fan R, Kiemen AL, Wu PH, Wirtz D. Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.13.571595. [PMID: 38168186 PMCID: PMC10760159 DOI: 10.1101/2023.12.13.571595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Chimeric antigen receptor (CAR) T cells express antigen-specific synthetic receptors, which upon binding to cancer cells, elicit T cell anti-tumor responses. CAR T cell therapy has enjoyed success in the clinic for hematological cancer indications, giving rise to decade-long remissions in some cases. However, CAR T therapy for patients with solid tumors has not seen similar success. Solid tumors constitute 90% of adult human cancers, representing an enormous unmet clinical need. Current approaches do not solve the central problem of limited ability of therapeutic cells to migrate through the stromal matrix. We discover that T cells at low and high density display low- and high-migration phenotypes, respectively. The highly migratory phenotype is mediated by a paracrine pathway from a group of self-produced cytokines that include IL5, TNFα, IFNγ, and IL8. We exploit this finding to "lock-in" a highly migratory phenotype by developing and expressing receptors, which we call velocity receptors (VRs). VRs target these cytokines and signal through these cytokines' cognate receptors to increase T cell motility and infiltrate lung, ovarian, and pancreatic tumors in large numbers and at doses for which control CAR T cells remain confined to the tumor periphery. In contrast to CAR therapy alone, VR-CAR T cells significantly attenuate tumor growth and extend overall survival. This work suggests that approaches to the design of immune cell receptors that focus on migration signaling will help current and future CAR cellular therapies to infiltrate deep into solid tumors.
Collapse
Affiliation(s)
- Adrian C Johnston
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | | | - Cameron C Lee
- Department of Biomedical Engineering, Johns Hopkins University
| | - Payal V Patel
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - Eban A Hanna
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - Eduarda Vaz
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - André Forjaz
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - Zeqi Wan
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
| | - Praful R Nair
- Institute for NanoBioTechnology, Johns Hopkins University
| | - Yeongseo Lim
- Department of Biomedical Engineering, Johns Hopkins University
| | - Tina Chen
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - Wenxuan Du
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
| | - Dongjoo Kim
- Department of Biomedical Engineering, Yale University
| | - Tushar D Nichakawade
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
- Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University
| | - Vito W Rebecca
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
| | - Challice L Bonifant
- Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University
| | - Rong Fan
- Department of Biomedical Engineering, Yale University
| | - Ashley L Kiemen
- Institute for NanoBioTechnology, Johns Hopkins University
- Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins University
- Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University
| | - Pei-Hsun Wu
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
- Institute for NanoBioTechnology, Johns Hopkins University
| | - Denis Wirtz
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University
- Institute for NanoBioTechnology, Johns Hopkins University
- Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins University
- Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University
| |
Collapse
|
|
25
|
Sun D, Shi X, Li S, Wang X, Yang X, Wan M. CAR‑T cell therapy: A breakthrough in traditional cancer treatment strategies (Review). Mol Med Rep 2024; 29:47. [PMID: 38275119 PMCID: PMC10835665 DOI: 10.3892/mmr.2024.13171] [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: 10/09/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
Chimeric antigen receptor (CAR)‑T cell therapy is an innovative approach to immune cell therapy that works by modifying the T cells of a patient to express the CAR protein on their surface, and thus induce their recognition and destruction of cancer cells. CAR‑T cell therapy has shown some success in treating hematological tumors, but it still faces a number of challenges in the treatment of solid tumors, such as antigen selection, tolerability and safety. In response to these issues, studies continue to improve the design of CAR‑T cells in pursuit of improved therapeutic efficacy and safety. In the future, CAR‑T cell therapy is expected to become an important cancer treatment, and may provide new ideas and strategies for individualized immunotherapy. The present review provides a comprehensive overview of the principles, clinical applications, therapeutic efficacy and challenges of CAR‑T cell therapy.
Collapse
Affiliation(s)
- Dahua Sun
- Department of General Surgery, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| | - Xiang Shi
- Department of Pathology, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| | - Sanyan Li
- Department of Pathology, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| | - Xiaohua Wang
- Department of Obstetrics, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| | - Xiao Yang
- Department of General Surgery, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| | - Meiping Wan
- Department of Traditional Chinese Medicine, Qianjiang Central Hospital, Qianjiang, Hubei 433100, P.R. China
| |
Collapse
|
|
26
|
Kronig MN, Wehrli M, Salas-Benito D, Maus MV. "Hurdles race for CAR T-cell therapy in digestive tract cancer". Immunol Rev 2023; 320:100-119. [PMID: 37694970 PMCID: PMC10846098 DOI: 10.1111/imr.13273] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/12/2023]
Abstract
Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients with pancreatic cancer. Even though immunotherapy such as immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid cancer types, ICI are still restricted to a very small group of patients and seem to be more efficacious in combination with chemotherapy. Cellular immunotherapy such as CAR T-cell therapy has entered clinical routine in hematological malignancies with outstanding results. There is growing interest on translating this kind of immunotherapy and success into patients with solid malignancies, such as DTC. This review attempts to describe the major advances in preclinical and clinical research with CAR T cells in DTC, considering the most relevant hurdles in each subtype of DTC.
Collapse
Affiliation(s)
- Marie-Noelle Kronig
- Department of Medical Oncology, Inselspital, Bern
University Hospital, University of Bern, Switzerland
| | - Marc Wehrli
- Department of Medical Oncology, Inselspital, Bern
University Hospital, University of Bern, Switzerland
- Cancer Center, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, U.S.A
- Cellular Immunotherapy Program, Cancer Center,
Massachusetts General Hospital, Harvard Medical School; Boston, MA, USA
| | - Diego Salas-Benito
- Cancer Center, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, U.S.A
- Cellular Immunotherapy Program, Cancer Center,
Massachusetts General Hospital, Harvard Medical School; Boston, MA, USA
| | - Marcela V. Maus
- Cancer Center, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, U.S.A
- Cellular Immunotherapy Program, Cancer Center,
Massachusetts General Hospital, Harvard Medical School; Boston, MA, USA
| |
Collapse
|
|
27
|
Thomas EM, Wright JA, Blake SJ, Page AJ, Worthley DL, Woods SL. Advancing translational research for colorectal immuno-oncology. Br J Cancer 2023; 129:1442-1450. [PMID: 37563222 PMCID: PMC10628092 DOI: 10.1038/s41416-023-02392-x] [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: 12/08/2022] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.
Collapse
Affiliation(s)
- Elaine M Thomas
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Josephine A Wright
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stephen J Blake
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Amanda J Page
- School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
- Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Daniel L Worthley
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Susan L Woods
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
| |
Collapse
|
|
28
|
He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
Collapse
Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| |
Collapse
|
|
29
|
Dabas P, Danda A. Revolutionizing cancer treatment: a comprehensive review of CAR-T cell therapy. Med Oncol 2023; 40:275. [PMID: 37608202 DOI: 10.1007/s12032-023-02146-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/01/2023] [Indexed: 08/24/2023]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy is a promising new treatment for cancer that involves genetically modifying a patient's T-cells to recognize and attack cancer cells. This review provides an overview of the latest discoveries and clinical trials related to CAR-T cell therapy, as well as the concept and applications of the therapy. The review also discusses the limitations and potential side effects of CAR-T cell therapy, including the high cost and the risk of cytokine release syndrome and neurotoxicity. While CAR-T cell therapy has shown promising results in the treatment of hematologic malignancies, ongoing research is needed to improve the efficacy and safety of the therapy and expand its use to solid tumors. With continued research and development, CAR-T cell therapy has the potential to revolutionize cancer treatment and improve outcomes for patients with cancer.
Collapse
Affiliation(s)
- Preeti Dabas
- St Jude Children's Research Hospital, Memphis, TN, USA.
| | - Adithi Danda
- St Jude Children's Research Hospital, Memphis, TN, USA
| |
Collapse
|
|
30
|
Stampone E, Bencivenga D, Capellupo MC, Roberti D, Tartaglione I, Perrotta S, Della Ragione F, Borriello A. Genome editing and cancer therapy: handling the hypoxia-responsive pathway as a promising strategy. Cell Mol Life Sci 2023; 80:220. [PMID: 37477829 PMCID: PMC10361942 DOI: 10.1007/s00018-023-04852-2] [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: 05/02/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/22/2023]
Abstract
The precise characterization of oxygen-sensing pathways and the identification of pO2-regulated gene expression are both issues of critical importance. The O2-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
Collapse
Affiliation(s)
- Emanuela Stampone
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Debora Bencivenga
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Maria Chiara Capellupo
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Domenico Roberti
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Immacolata Tartaglione
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Silverio Perrotta
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Fulvio Della Ragione
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
| |
Collapse
|
|
31
|
Zheng Z, Li S, Liu M, Chen C, Zhang L, Zhou D. Fine-Tuning through Generations: Advances in Structure and Production of CAR-T Therapy. Cancers (Basel) 2023; 15:3476. [PMID: 37444586 DOI: 10.3390/cancers15133476] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has seen significant advancements in the past few decades. It involves genetically modifying T cells to target cancer cells expressing specific antigens, providing a novel approach to treating various types of cancer. However, the initial success of first-generation CAR-T cells was limited due to inadequate proliferation and undesirable outcomes. Nonetheless, significant progress has been made in CAR-T cell engineering, leading to the development of the latest fifth-generation CAR-T cells that can target multiple antigens and overcome individual limitations. Despite these advancements, some shortcomings prevent the widespread use of CAR-T therapy, including life-threatening toxicities, T-cell exhaustion, and inadequate infiltration for solid tumors. Researchers have made considerable efforts to address these issues by developing new strategies for improving CAR-T cell function and reducing toxicities. This review provides an overview of the path of CAR-T cell development and highlights some of the prominent advances in its structure and manufacturing process, which include the strategies to improve antigen recognition, enhance T-cell activation and persistence, and overcome immune escape. Finally, the review briefly covers other immune cells for cancer therapy and ends with the discussion on the broad prospects of CAR-T in the treatment of various diseases, not just hematological tumors, and the challenges that need to be addressed for the widespread clinical application of CAR-T cell therapies.
Collapse
Affiliation(s)
- Zhibo Zheng
- Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Siyuan Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mohan Liu
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Chuyan Chen
- Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100730, China
| | - Lu Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Daobin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| |
Collapse
|
|
32
|
Garza Treviño EN, Quiroz Reyes AG, Rojas Murillo JA, de la Garza Kalife DA, Delgado Gonzalez P, Islas JF, Estrada Rodriguez AE, Gonzalez Villarreal CA. Cell Therapy as Target Therapy against Colon Cancer Stem Cells. Int J Mol Sci 2023; 24:ijms24098163. [PMID: 37175871 PMCID: PMC10179203 DOI: 10.3390/ijms24098163] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting CSCs is a promising strategy to eliminate the propagation of tumor cells and impair overall tumor development. Recent research shows that several immune cells play a crucial role in regulating tumor cell proliferation by regulating different CSC maintenance or proliferation pathways. There have been great advances in cellular immunotherapy using T cells, natural killer (NK) cells, macrophages, or stem cells for the selective targeting of tumor cells or CSCs in colorectal cancer (CRC). This review summarizes the CRC molecular profiles that may benefit from said therapy and the main vehicles used in cell therapy against CSCs. We also discuss the challenges, limitations, and advantages of combining conventional and/or current targeted treatments in the late stages of CRC.
Collapse
Affiliation(s)
- Elsa N Garza Treviño
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Adriana G Quiroz Reyes
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Juan Antonio Rojas Murillo
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - David A de la Garza Kalife
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Paulina Delgado Gonzalez
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Jose F Islas
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Ana Esther Estrada Rodriguez
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500. Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
| | - Carlos A Gonzalez Villarreal
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500. Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
| |
Collapse
|
|
33
|
Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol Sci 2023; 44:222-236. [PMID: 36828759 PMCID: PMC10365888 DOI: 10.1016/j.tips.2023.01.003] [Citation(s) in RCA: 165] [Impact Index Per Article: 82.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/25/2023]
Abstract
Metastatic colorectal cancer (mCRC) remains a lethal disease with an approximately 14% 5-year survival rate. While early-stage colorectal cancer (CRC) can be cured by surgery with or without adjuvant chemotherapy, mCRC cannot be eradicated due to a large burden of disseminated cancer cells comprising therapy-resistant metastasis-competent cells. To address this gap, recent studies have focused on further elucidating the molecular mechanisms underlying colorectal metastasis and recognizing the limitations of available therapeutic interventions. In this review, we discuss newfound factors that regulate CRC cell dissemination and colonization of distant organs, such as genetic mutations, identification of metastasis-initiating cells (MICs), epithelial-mesenchymal transition (EMT), and the tumor microenvironment (TME). We also review current treatments for mCRC, therapeutic regimens undergoing clinical trials, and trending preclinical studies being investigated to target treatment-resistant mCRC.
Collapse
Affiliation(s)
- Alice E Shin
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Filippo G Giancotti
- Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
| |
Collapse
|
|
34
|
Yan T, Zhu L, Chen J. Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment. Exp Hematol Oncol 2023; 12:14. [PMID: 36707873 PMCID: PMC9883880 DOI: 10.1186/s40164-023-00373-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 01/10/2023] [Indexed: 01/28/2023] Open
Abstract
The past decade has witnessed ongoing progress in immune therapy to ameliorate human health. As an emerging technique, chimeric antigen receptor (CAR) T-cell therapy has the advantages of specific killing of cancer cells, a high remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to target diversity, tumor heterogeneity, and the complex microenvironment. In this review, we have outlined the development of the CAR T-cell technique, summarized the current advances in tumor-associated antigens (TAAs), and highlighted the importance of tumor-specific antigens (TSAs) or neoantigens for solid tumors. We also addressed the challenge of the TAA binding domain in CARs to overcome off-tumor toxicity. Moreover, we illustrated the dominant tumor microenvironment (TME)-induced challenges and new strategies based on TME-associated antigens (TMAs) for solid tumor CAR T-cell therapy.
Collapse
Affiliation(s)
- Ting Yan
- grid.443397.e0000 0004 0368 7493Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311 Hainan China
| | - Lingfeng Zhu
- grid.443397.e0000 0004 0368 7493Department of Urology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311 Hainan China
| | - Jin Chen
- grid.443397.e0000 0004 0368 7493Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311 Hainan China ,grid.443397.e0000 0004 0368 7493Department of Clinical Laboratory, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311 Hainan China
| |
Collapse
|
|
35
|
Yoshikawa A, Nakamura Y. Molecular Basis of HER2-Targeted Therapy for HER2-Positive Colorectal Cancer. Cancers (Basel) 2022; 15:183. [PMID: 36612185 PMCID: PMC9818808 DOI: 10.3390/cancers15010183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) amplification has emerged as a biomarker in colorectal cancer (CRC), occurring in 1-4% of metastatic CRC (mCRC). In addition to conventional methods, such as immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing-based tissue or circulating tumor DNA analysis has recently been used to identify HER2 amplification and assess HER2 overexpression. Prospective clinical trials have demonstrated the efficacy of HER2-targeted therapies in HER2-positive mCRC. The TRIUMPH study, a phase II study of dual HER2 antibodies, i.e., pertuzumab plus trastuzumab, demonstrated promising efficacy for patients with HER2-positive mCRC confirmed by tissue-and/or blood-based techniques, which led to the regulatory approval of this combination therapy in Japan. The mechanisms associated with efficacy and resistance have also been explored in translational studies that incorporate liquid biopsy in prospective trials. In particular, HER2 copy number and co-alterations have repeatedly been reported as biomarkers related to efficacy. To improve the therapeutic efficacy of the current strategy, many clinical trials with various HER2-targeted agents are ongoing. This review discusses the molecular basis of HER2-targeted therapeutic strategies for patients with HER2-positive mCRC.
Collapse
Affiliation(s)
- Ayumu Yoshikawa
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa 277-0882, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa 277-0882, Japan
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa 277-0882, Japan
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa 277-0882, Japan
| |
Collapse
|
|
36
|
Ghazi B, El Ghanmi A, Kandoussi S, Ghouzlani A, Badou A. CAR T-cells for colorectal cancer immunotherapy: Ready to go? Front Immunol 2022; 13:978195. [PMID: 36458008 PMCID: PMC9705989 DOI: 10.3389/fimmu.2022.978195] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/14/2022] [Indexed: 08/12/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.
Collapse
Affiliation(s)
- Bouchra Ghazi
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Adil El Ghanmi
- Mohammed VI International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| |
Collapse
|
|
37
|
Wang N, Cao Y, Si C, Shao P, Su G, Wang K, Bao J, Yang L. Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies. Cancers (Basel) 2022; 14:5160. [PMID: 36291943 PMCID: PMC9600272 DOI: 10.3390/cancers14205160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 12/24/2022] Open
Abstract
Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.
Collapse
Affiliation(s)
- Nannan Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Yuepeng Cao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Chengshuai Si
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Peng Shao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Guoqing Su
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Ke Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Jun Bao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Liu Yang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| |
Collapse
|
|
38
|
Qu C, Zhang H, Cao H, Tang L, Mo H, Liu F, Zhang L, Yi Z, Long L, Yan L, Wang Z, Zhang N, Luo P, Zhang J, Liu Z, Ye W, Liu Z, Cheng Q. Tumor buster - where will the CAR-T cell therapy 'missile' go? Mol Cancer 2022; 21:201. [PMID: 36261831 PMCID: PMC9580202 DOI: 10.1186/s12943-022-01669-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies’ clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.
Collapse
Affiliation(s)
- Chunrun Qu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,XiangYa School of Medicine, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hui Cao
- Department of Psychiatry, The Second People's Hospital of Hunan Province, The Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.,The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Lanhua Tang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haoyang Mo
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,XiangYa School of Medicine, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,XiangYa School of Medicine, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lifu Long
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,XiangYa School of Medicine, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Luzhe Yan
- XiangYa School of Medicine, Central South University, Changsha, Hunan, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Nan Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,One-third Lab, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Weijie Ye
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| |
Collapse
|
|
39
|
Yuan J, Li J, Gao C, Jiang C, Xiang Z, Wu J. Immunotherapies catering to the unmet medical need of cold colorectal cancer. Front Immunol 2022; 13:1022190. [PMID: 36275766 PMCID: PMC9579278 DOI: 10.3389/fimmu.2022.1022190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
As a common malignant tumor of gastrointestinal tract, the incidence of colorectal cancer (CRC) has gradually increased in recent years. In western developed countries, it has even become the second largest malignant tumor next to lung cancer. Immunotherapy is a hot topic in the field of cancer therapy, including immune checkpoint blockade (ICB), adoptive cell therapy (ACT), cancer vaccines and cytokines, aiming to improve the ability of the immune system to recognize, target and eliminate cancer cells. However, cold CRC, which accounts for a high proportion of CRC, is not so reactive to it. The development of immunotherapy to prevent cancer cells from forming “immune escape” pathways to the immune system in cold CRC, has been under increasing study attention. There is proof that an organic combination of radiotherapy, chemotherapy, and several immunotherapies can considerably boost the immune system’s capacity to eradicate tumor cells. In this review, we summarized the role of immunotherapy in colorectal cancer. In addition, we propose a breakthrough and strategy to improve the role of immunotherapy in cold CRC based on its characteristics.
Collapse
Affiliation(s)
- Jun Yuan
- Department of Clinical Laboratory, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, China
| | - Jiarui Li
- Zhejiang University School of Medicine, Hangzhou, China
| | - Ce Gao
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Chun Jiang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Jian Wu, ; Ze Xiang,
| | - Jian Wu
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
- *Correspondence: Jian Wu, ; Ze Xiang,
| |
Collapse
|
|
40
|
Dai Z, Fu J, Peng X, Tang D, Song J. Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy. Cancers (Basel) 2022; 14:4796. [PMID: 36230724 PMCID: PMC9564057 DOI: 10.3390/cancers14194796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
In recent years, cancer immunotherapy has become a breakthrough method to solve solid tumors. It uses immune checkpoint inhibitors to interfere with tumor immune escape to coordinate anti-tumor therapy. However, immunotherapy has an individualized response rate. Moreover, immune-related adverse events and drug resistance are still urgent issues that need to be resolved, which may be attributed to the immune imbalance caused by immune checkpoint inhibitors. Microbiome research has fully revealed the metabolic-immune interaction relationship between the microbiome and the host. Surprisingly, sequencing technology further proved that intestinal microbiota could effectively intervene in tumor immunotherapy and reduce the incidence of adverse events. Therefore, cancer immunotherapy under the intervention of intestinal microbiota has innovatively broadened the anti-tumor landscape and is expected to become an active strategy to enhance individualized responses.
Collapse
Affiliation(s)
- Zhujiang Dai
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai 200092, China
| | - Jihong Fu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai 200092, China
| | - Xiang Peng
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai 200092, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Jinglue Song
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai 200092, China
| |
Collapse
|
|
41
|
Qin X, Wu F, Chen C, Li Q. Recent advances in CAR-T cells therapy for colorectal cancer. Front Immunol 2022; 13:904137. [PMID: 36238297 PMCID: PMC9551069 DOI: 10.3389/fimmu.2022.904137] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 09/09/2022] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer, with a high mortality rate and a serious impact on people’s life and health. In recent years, adoptive chimeric antigen receptor T (CAR-T) cells therapy has shown well efficacy in the treatment of hematological malignancies, but there are still many problems and challenges in solid tumors such as CRC. For example, the tumor immunosuppressive microenvironment, the low targeting of CAR-T cells, the short time of CAR-T cells in vivo, and the limited proliferation capacity of CAR-T cells, CAR-T cells can not effectively infiltrate into the tumor and so on. New approaches have been proposed to address these challenges in CRC, and this review provides a comprehensive overview of the current state of CAR-T cells therapy in CRC.
Collapse
Affiliation(s)
- Xiaoling Qin
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Fengjiao Wu
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chang Chen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Department of Pharmacology, Harbin Medical University, Harbin, China
- *Correspondence: Qi Li, ; Chang Chen,
| | - Qi Li
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Qi Li, ; Chang Chen,
| |
Collapse
|
|
42
|
Torres-Jiménez J, Esteban-Villarrubia J, Ferreiro-Monteagudo R. Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene. Cancers (Basel) 2022; 14:3718. [PMID: 35954382 PMCID: PMC9367374 DOI: 10.3390/cancers14153718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. ERBB2 amplification (also known as HER-2) has been identified in 2-3% of patients with mCRC, but there are currently no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the molecular structure of ERBB2, clinical features of these patients, diagnosis of ERBB2 alterations, and the most relevant clinical trials with ERBB2-targeted therapies in mCRC.
Collapse
Affiliation(s)
- Javier Torres-Jiménez
- Medical Oncology Department, MD Anderson Cancer Center Madrid, 28033 Madrid, Spain
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
| | - Jorge Esteban-Villarrubia
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
- Medical Oncology Department, University Hospital 12 de Octubre, 28041 Madrid, Spain
| | - Reyes Ferreiro-Monteagudo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
| |
Collapse
|
|
43
|
Achalla LSV, Shinde RK, Jogdand S, Vodithala S. Review of the Role of HER2/neu in Colorectal Carcinomas. Cureus 2022; 14:e25409. [PMID: 35774672 PMCID: PMC9236668 DOI: 10.7759/cureus.25409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2022] [Indexed: 11/22/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2/neu) is an oncogenic driver and a proven target for treatment of breast and gastric cancers. The role of HER2/neu and its blockage in various tumors, particularly colorectal adenocarcinoma has been widely explored following the revolutionary impact of anti-HER2/neu therapy in breast and gastric carcinoma patients. This review aimed to highlight the most recent updates on the significance of HER2/neu as a prognostic and predictive factor in these tumors together with its subsequent possible therapeutic indications from preclinical tests and ongoing assessments testing anti-HER2/neu agents in colorectal carcinoma (CRC). In the near future with a growingly tailored therapeutic approach toward cancers, HER2/neu targeted therapeutic strategies may blend into CRC treatment methods.
Collapse
|
|
44
|
Rosati G, Aprile G, Colombo A, Cordio S, Giampaglia M, Cappetta A, Porretto CM, De Stefano A, Bilancia D, Avallone A. Colorectal Cancer Heterogeneity and the Impact on Precision Medicine and Therapy Efficacy. Biomedicines 2022; 10:1035. [PMID: 35625772 PMCID: PMC9138254 DOI: 10.3390/biomedicines10051035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/16/2022] [Accepted: 04/28/2022] [Indexed: 12/02/2022] Open
Abstract
Novel targeted therapies for metastatic colorectal cancer are needed to personalize treatments by guiding specific biomarkers selected on the genetic profile of patients. RAS and BRAF inhibitors have been developed for patients who become unresponsive to standard therapies. Sotorasib and adagrasib showed promising results in phase I/II basket trial and a phase III trial was planned with a combination of these RAS inhibitors and anti-EGFR monoclonal antibodies. Encorafenib and binimetinib were administered in phase II clinical trials for BRAF mutated patients. Pembrolizumab is now recommended in patients exhibiting microsatellite instability. Larotrectinib and entrectinib showed a fast and durable response with few and reversible adverse events in cases with NTRK fusions. Trastuzumab and trastuzumab deruxtecan exhibited promising and durable activity in HER-2-positive patients. In this review, the reasons for an extension of the molecular profile of patients were assessed and placed in the context of the advancements in the understanding of genetics. We highlight the differential effect of new targeted therapies through an ever-deeper characterization of tumor tissue. An overview of ongoing clinical trials is also provided.
Collapse
Affiliation(s)
- Gerardo Rosati
- Medical Oncology Unit, “S. Carlo” Hospital, 85100 Potenza, Italy; (M.G.); (D.B.)
| | - Giuseppe Aprile
- Department of Oncology, “San Bortolo” General Hospital, Azienda ULSS8 Berica, 36100 Vicenza, Italy; (G.A.); (A.C.)
| | - Alfredo Colombo
- Medical Oncology Unit, CDC Macchiarella, 90138 Palermo, Italy; (A.C.); (C.M.P.)
| | - Stefano Cordio
- Medical Oncology Unit, “Maria Paternò Arezzo” Hospital, 97100 Ragusa, Italy;
| | - Marianna Giampaglia
- Medical Oncology Unit, “S. Carlo” Hospital, 85100 Potenza, Italy; (M.G.); (D.B.)
| | - Alessandro Cappetta
- Department of Oncology, “San Bortolo” General Hospital, Azienda ULSS8 Berica, 36100 Vicenza, Italy; (G.A.); (A.C.)
| | | | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori IRCCS-Fondazione “G. Pascale”, 80121 Napoli, Italy;
| | - Domenico Bilancia
- Medical Oncology Unit, “S. Carlo” Hospital, 85100 Potenza, Italy; (M.G.); (D.B.)
| | - Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori IRCCS-Fondazione “G. Pascale”, 80121 Napoli, Italy;
| |
Collapse
|