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Wang T, Shi X, Xu X, Zhang J, Ma Z, Meng C, Jiao D, Wang Y, Chen Y, He Z, Zhu Y, Liu HN, Zhang T, Jiang Q. Emerging prodrug and nano-drug delivery strategies for the detection and elimination of senescent tumor cells. Biomaterials 2025; 318:123129. [PMID: 39922127 DOI: 10.1016/j.biomaterials.2025.123129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/15/2025] [Accepted: 01/23/2025] [Indexed: 02/10/2025]
Abstract
Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.
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Affiliation(s)
- Tao Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xianbao Shi
- Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Xiaolan Xu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jiaming Zhang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhengdi Ma
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Chen Meng
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dian Jiao
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yubo Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yanfei Chen
- School of Hainan Provincial Drug Safety Evaluation Research Center, Hainan Medical University, Haikou, China
| | - Zhonggui He
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Ying Zhu
- Department of Neurology, The First Hospital of China Medical University, Shenyang, 110002, China.
| | - He-Nan Liu
- Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Tianhong Zhang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Qikun Jiang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Medical University, Haikou, China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, China.
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2
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Jahandar-Lashaki S, Farajnia S, Faraji-Barhagh A, Hosseini Z, Bakhtiyari N, Rahbarnia L. Phage Display as a Medium for Target Therapy Based Drug Discovery, Review and Update. Mol Biotechnol 2025; 67:2161-2184. [PMID: 38822912 DOI: 10.1007/s12033-024-01195-6] [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: 11/01/2023] [Accepted: 05/07/2024] [Indexed: 06/03/2024]
Abstract
Phage libraries are now amongst the most prominent approaches for the identification of high-affinity antibodies/peptides from billions of displayed phages in a specific library through the biopanning process. Due to its ability to discover potential therapeutic candidates that bind specifically to targets, phage display has gained considerable attention in targeted therapy. Using this approach, peptides with high-affinity and specificity can be identified for potential therapeutic or diagnostic use. Furthermore, phage libraries can be used to rapidly screen and identify novel antibodies to develop immunotherapeutics. The Food and Drug Administration (FDA) has approved several phage display-derived peptides and antibodies for the treatment of different diseases. In the current review, we provided a comprehensive insight into the role of phage display-derived peptides and antibodies in the treatment of different diseases including cancers, infectious diseases and neurological disorders. We also explored the applications of phage display in targeted drug delivery, gene therapy, and CAR T-cell.
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Affiliation(s)
- Samaneh Jahandar-Lashaki
- Medical Biotechnology Department, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Safar Farajnia
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Aref Faraji-Barhagh
- Medical Biotechnology Department, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Hosseini
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Nasim Bakhtiyari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Rahbarnia
- Infectious and Tropical Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Sadeghi M, Kareva I, Pogudin G, Sontag ED. Quantitative Pharmacology Methods for Bispecific T Cell Engagers. Bull Math Biol 2025; 87:85. [PMID: 40413295 DOI: 10.1007/s11538-025-01455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 04/23/2025] [Indexed: 05/27/2025]
Abstract
T Cell Engager (TCE)s are an exciting therapeutic modality in immuno-oncology that acts to bypass antigen presentation and forms a direct link between cancer and immune cells in the Tumor Microenvironment (TME). TCEs are efficacious only when the drug is bound to both immune and cancer cell targets. Therefore, approaches that maximize the formation of the drug-target trimer in the TME are expected to increase the drug's efficacy. In this study, we quantitatively investigate how the concentration of ternary complex and its biodistribution depend on both the targets' specific properties and the design characteristics of the TCE, and specifically on the binding kinetics of the drug to its targets. A simplified mathematical model of drug-target interactions is considered here, with insights from the "three-body" problem applied to the model. Parameter identifiability analysis performed on the model demonstrates that steady state data, which is often available at the early pre-clinical stages, is sufficient to estimate the binding affinity of the TCE molecule to both targets. We used the model to analyze several existing antibodies, both clinically approved and under development, to explore their common kinetic features. The manuscript concludes with an assessment of a full quantitative pharmacology model that accounts for drug disposition into the peripheral compartment.
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Affiliation(s)
- Mahdiar Sadeghi
- Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA
- Quantitative Pharmacology, EMD Serono Inc, Merck KGaA, Billerica, Massachusetts, USA
| | - Irina Kareva
- Quantitative Pharmacology, EMD Serono Inc, Merck KGaA, Billerica, Massachusetts, USA
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Gleb Pogudin
- LIX, CNRS, École Polytechnique, Institute Polytechnique de Paris, Palaiseau, France
| | - Eduardo D Sontag
- Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA.
- Department of Bioengineering, Northeastern University, Boston, MA, USA.
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
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4
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Wu W, Liu B, Zhang Q, Zhang X, Feng P, Jia Y, Xue X. Heterogeneity and efficacy of immunotherapy in multiple cancer: insights from a meta-analysis. Biol Proced Online 2025; 27:17. [PMID: 40389815 PMCID: PMC12090696 DOI: 10.1186/s12575-025-00274-5] [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: 12/13/2024] [Accepted: 03/24/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Immunotherapy has been recognized as a significant advancement in cancer treatment by promoting the body's immune system to identify and eliminate cancer cells more effectively. Unlike conventional therapies, immunotherapy can enhance the natural capabilities of human immune system. Chimeric Antigen Receptor T-cell (CAR-T) therapy involves genetical-modified T-cells from patients to better catch and attack cancer cells. Up to date, CAR-T therapy has shown particular promise in treating certain types of leukemia and lymphoma, highlighting the transformative potential of immunotherapy. RESULTS Literature data search using PubMed, CNKI, and Wanfang were searched to collect eligible studies up to January 2025. The primary outcomes of complete response rate (CRR), objective response rate (ORR), dead rate (DR), and other adverse reactions were evaluated. Secondary outcomes (CRR, ORR, and DR) of subgroup analysis from different cancer types, origins, and outcomes for survival rate were analyzed for our final results. A total of 649 studies were initially identified through database searching. After removing duplicates and non-clinical cancer studies, 32 eligible studies were included in this work. The pooled data included 819 patients for objective response rate (ORR), 843 patients for complete response rate (CRR), and 868 patients for dead event. In the included studies, 24 reported ORR data, revealing an objective response rate of 84.86% (695/819) with little heterogeneity (OR: 0.87, 95% CI 0.80-0.91, P = < 0.01, I2 = 61%); 24 studies showed a CRR of 65.30% (491/843) with significant heterogeneity (OR: 0.58, 95% CI: 0.43-0.72, P < 0.01, I2 = 84%); 27 studies showed a mortality rate of 23.73% (206/868) with significant heterogeneity (OR: 0.19, 95% CI: 0.11-0.32, P < 0.01, I2 = 77%). Subgroup analysis based on cancer type revealed that ORR was higher in multiple myeloma (86.77%, 400/461) compared with leukemia (84.92%, 259/305) and lymphoma (67.92%, 36/53). In parallel, heterogeneity observed based on case origins suggested that Chinese cases showed significantly higher ORR, CRR, and survival rates compared with American ones. CONCLUSIONS This meta-analysis provides valuable insights into the potential of immunotherapy, particularly CAR-T, in cancer treatment. Findings showed the different efficacy and safety of immunotherapy in treating multiple cancers, with various objective response rates. Continued studies from more trials with different populations are needed to optimize their efficacy in further cancer treatment and precision medicine.
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Affiliation(s)
- Weidong Wu
- Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Bin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qing Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaojuan Zhang
- Scientific Research and Discipline Management Office, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengya Feng
- Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
- Department of Children Rehabilitation Medicine, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Yongliang Jia
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| | - Xia Xue
- Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
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Li M, Wang X, He W, Zhou H. Drug-tolerant persister cells in acute myeloid leukemia: pressing challenge and promising new strategies for treatment. Front Med (Lausanne) 2025; 12:1586552. [PMID: 40443513 PMCID: PMC12120853 DOI: 10.3389/fmed.2025.1586552] [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: 03/04/2025] [Accepted: 04/28/2025] [Indexed: 06/02/2025] Open
Abstract
Acute myeloid leukemia (AML) exhibits a pronounced ability to develop drug resistance and undergo disease relapse. Recent research has noticed that resistance to treatments could substantially be attributed to drug-tolerant persister (DTP) cells, which are capable of surviving under therapeutic pressures. These are transient, reversibly dormant cells with the capability to act as a reservoir for disease relapse. DTP cells utilize diverse adaptive strategies to optimize the ecological niche, undergo metabolic reprogramming, and interact with microenvironment. The persister state of AML is established through transient cellular reprogramming, thus allowing cells to survive the initial phase of drug therapy and develop drug resistance. Our review explores the identification and phenotypic characteristics of AML DTP cells, as well as their clinical relevance. We summarize the mechanisms underlying the persistence of AML DTP cells and the molecular attributes that define the DTP state. We further address the current challenges and future prospects of DTP-targeting approaches. Understanding these features may provide critical insights into novel therapeutic strategies aimed at targeting AML DTP cells, especially in the new era of immunotherapy against AML.
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Affiliation(s)
- Meng Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjuan He
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Zhou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Bains RS, Raju TG, Semaan LC, Block A, Yamaguchi Y, Priceman SJ, George SC, Shirure VS. Vascularized tumor-on-a-chip to investigate immunosuppression of CAR-T cells. LAB ON A CHIP 2025; 25:2390-2400. [PMID: 40289711 DOI: 10.1039/d4lc01089b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy, effective in blood cancers, shows limited success in solid tumors, such as prostate, pancreatic, and brain cancers due, in part, to an immunosuppressive tumor microenvironment (TME). Immunosuppression affects various cell types, including tumor cells, macrophages, and endothelial cells. Conventional murine-based models offer limited concordance with human immunology and cancer biology. Therefore, we have developed a human "tumor-on-a-chip" (TOC) platform to model elements of immunosuppression at high spatiotemporal resolution. Our TOC features an endothelial cell-lined channel that mimics features of an in vivo capillary, such as cell attachment and extravasation across the endothelium and into the TME. Using 70 kDa dextran and fluorescence-recovery-after-photobleaching (FRAP), we confirmed physiologic interstitial flow velocities (0.1-1 μm s-1). Our device demonstrates that tumor-derived factors can diffuse in the opposite direction of interstitial flow to reach the endothelium up to 200 μm away, and at concentrations as high as 20% of those at the tumor margin. M2-like immunosuppressive macrophages and endothelial cells affect prostate tumor cell growth, clustering, and migration. M2-like macrophages also induce PD-L1 and inhibit ICAM-1 gene expression on the adjacent endothelium in a pattern that limits CAR-T cell extravasation and effector function. This observation is abrogated in the presence of the anti-PD-L1 drug atezolizumab. These results provide mechanistic insight for in vivo observations showing limited CAR-T cell extravasation and effector function in solid tumors. Furthermore, they point to a specific role of M2 macrophages in driving CAR-T cell migration into and within the TME and could prove useful in the development of novel therapies to improve solid tumor CAR-T cell therapies.
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Affiliation(s)
- Rajul S Bains
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
| | - Tara G Raju
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
| | - Layla C Semaan
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
| | - Anton Block
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
| | - Yukiko Yamaguchi
- Department of Medicine, KSOM/NCCC Center for Cancer Cellular Immunotherapy Research, University of Southern California, Los Angeles, CA, 90098, USA
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 91010, USA
| | - Saul J Priceman
- Department of Medicine, KSOM/NCCC Center for Cancer Cellular Immunotherapy Research, University of Southern California, Los Angeles, CA, 90098, USA
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 91010, USA
| | - Steven C George
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
- Department of Surgery, University of California, Davis,, Sacramento, CA, 95817, USA
| | - Venktesh S Shirure
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, 95616, USA.
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Liu F, Li K, Zhu Q. Targeting Metabolic Reprogramming in Bladder Cancer Immunotherapy: A Precision Medicine Approach. Biomedicines 2025; 13:1145. [PMID: 40426972 PMCID: PMC12108893 DOI: 10.3390/biomedicines13051145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 05/29/2025] Open
Abstract
Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic-immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer.
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Affiliation(s)
| | | | - Qingyi Zhu
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
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Wang Z, Hong H. Anti‑HER2‑targeted therapies for the treatment of advanced HER2‑positive breast cancer with brain metastases (Review). Mol Clin Oncol 2025; 22:45. [PMID: 40170686 PMCID: PMC11959222 DOI: 10.3892/mco.2025.2840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 02/17/2025] [Indexed: 04/03/2025] Open
Abstract
Compared with other metastatic sites, breast cancer brain metastases (BCBMs) are associated with the shortest survival time. In addition, human epidermal growth factor receptor 2 (HER2) is observed to be amplified in 20-25% of breast cancer cases where it is a poor prognostic factor for brain metastases. Various anti-HER2 targeted therapies have brought both new opportunities and challenges to patients with HER2-positive BCBM over the past decade. However, prolonging survival time and improving quality of life of patients have become controversial issues in the field of clinical research on BCBMs. On the basis of the latest literature, the present review documents the anti-HER2 targeted drugs applied in patients with HER2-positive BCBM. Further studies on the efficacy and safety of novel HER2-targeted drugs and combined or sequential therapy in clinical treatment are expected to provide more effective strategies for the treatment of patients with HER2-positive BCBM.
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Affiliation(s)
- Zhangyan Wang
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
| | - Huangming Hong
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
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Bhutani B, Sharma V, Ganguly NK, Rana R. Unravelling the modified T cell receptor through Gen-Next CAR T cell therapy in Glioblastoma: Current status and future challenges. Biomed Pharmacother 2025; 186:117987. [PMID: 40117901 DOI: 10.1016/j.biopha.2025.117987] [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: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025] Open
Abstract
PURPOSE Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity. METHODS In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy. FINDINGS To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes. IMPLICATIONS CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.
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Affiliation(s)
- Bhavya Bhutani
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vyoma Sharma
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
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10
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Rana M, Liou KC, Thakur A, Nepali K, Liou JP. Advancing glioblastoma therapy: Learning from the past and innovations for the future. Cancer Lett 2025; 617:217601. [PMID: 40037502 DOI: 10.1016/j.canlet.2025.217601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/25/2025] [Accepted: 03/01/2025] [Indexed: 03/06/2025]
Abstract
Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.
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Affiliation(s)
- Mandeep Rana
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan
| | - Ke-Chi Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan
| | - Amandeep Thakur
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, 110, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan.
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, 110, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan.
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11
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Zhang H, Sun F, Cao H, Yang L, Yang F, Chen R, Jiang S, Wang R, Yu X, Li B, Chu X. UBA protein family: An emerging set of E1 ubiquitin ligases in cancer-A review. Int J Biol Macromol 2025; 308:142277. [PMID: 40120894 DOI: 10.1016/j.ijbiomac.2025.142277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/12/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
The Ubiquitin A (UBA) protein family contains seven members that protect themselves or their interacting proteins from proteasome degradation. The UBA protein family regulates cell proliferation, cell cycle, invasion, migration, apoptosis, autophagy, tissue differentiation, and immune response. With the deepening of research, the UBA protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and have an important role in the prognosis of tumors. In this paper, we review the structure, biological process, target therapy, and biomarkers of the UBA protein family to provide new ideas for the diagnosis and treatment of tumors.
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Affiliation(s)
- Huhu Zhang
- Department of Cardiology, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao 266100, Shandong, China; Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Fulin Sun
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China
| | - Hongyu Cao
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China
| | - Lina Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Fanghao Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Ruolan Chen
- Department of Cardiology, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao 266100, Shandong, China
| | - Shuyao Jiang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China
| | - Ruixuan Wang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China
| | - Xin Yu
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China
| | - Bing Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
| | - Xianming Chu
- Department of Cardiology, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao 266100, Shandong, China.
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Jin M, Liu S, Zhan M, Huang JD. Engineered Genetic Circuits Activated by Bezafibrate Improve ESC-Based TAA Cancer Vaccine Efficacy and PD-L1 Nanobody Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2500272. [PMID: 40245119 DOI: 10.1002/advs.202500272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/01/2025] [Indexed: 04/19/2025]
Abstract
Immunotherapy targeting tumor antigens and immune checkpoint inhibitors has garnered significant attention in cancer treatment. Synthetic gene circuits are developed, encoded in plasmids, which regulate the expression of tumor antigens shared with embryonic stem cells (ESCs) and PD-L1 nanobody (PD-L1 nb) in response to bezafibrate stimulation. This approach significantly minimizes side effects and improved therapeutic efficacy. The transcriptional switches leverage the interaction between the bezafibrate-responsive transcriptional activator PPARγ and RXRα, which are fused with the VPR/VP64/p65 activation domains (AD) and the Gal4 DNA-binding domain (DBD), respectively. These synthetic constructs are validated and their ability to modulate gene expression upon bezafibrate treatment are confirmed. Notably, the gene expression is precise and tunable in response to bezafibrate administration. HEK293T cells or ESCs are employed to deliver this gene circuit, or the plasmids containing the circuit into the tumor are directly injected. Administration of bezafibrate reduces tumor growth, increases specific CD8+ T cells, and mitigates CD8+ T cell exhaustion, underscoring the feasibility and effectiveness of the approach. ESC-based and intratumoral delivery of the synthetic gene circuits and cargo genes, particularly PD-L1 nb, significantly inhibit tumor growth. PD-L1 nb effectively blocks PD-L1 expression both in vitro and in vivo, as confirmed by using a mutant PD-L1 nb sequence.
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Affiliation(s)
- Meiling Jin
- Chinese Academy of Sciences (CAS) Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Shuzhen Liu
- Chinese Academy of Sciences (CAS) Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Mingshuo Zhan
- Chinese Academy of Sciences (CAS) Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Jian-Dong Huang
- Chinese Academy of Sciences (CAS) Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, P. R. China
- Department of Clinical Oncology, Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, P. R. China
- Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen, 518057, P. R. China
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13
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Nie J, Zhou L, Tian W, Liu X, Yang L, Yang X, Zhang Y, Wei S, Wang DW, Wei J. Deep insight into cytokine storm: from pathogenesis to treatment. Signal Transduct Target Ther 2025; 10:112. [PMID: 40234407 PMCID: PMC12000524 DOI: 10.1038/s41392-025-02178-y] [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: 08/09/2024] [Revised: 12/22/2024] [Accepted: 02/12/2025] [Indexed: 04/17/2025] Open
Abstract
Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.
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Grants
- 82070217, 81873427 National Natural Science Foundation of China (National Science Foundation of China)
- 82100401 National Natural Science Foundation of China (National Science Foundation of China)
- 81772477, 81201848, 82473220 National Natural Science Foundation of China (National Science Foundation of China)
- 82330010,81630010,81790624 National Natural Science Foundation of China (National Science Foundation of China)
- National High Technology Research and Development Program of China, Grant number: 2021YFA1101500.
- The Hubei Provincial Natural Science Foundation (No.2024AFB050)
- Project of Shanxi Bethune Hospital, Grant Numbber: 2023xg02); Fundamental Research Program of Shanxi Province, Grant Numbber: 202303021211224
- The Key Scientific Research Project of COVID-19 Infection Emergency Treatment of Shanxi Bethune Hospital (2023xg01), 2023 COVID-19 Research Project of Shanxi Provincial Health Commission (No.2023XG001, No. 2023XG005), Four “Batches” Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province (2023XM003), Cancer special Fund research project of Shanxi Bethune Hospital (No. 2020-ZL04), and External Expert Workshop Fund Program of Shanxi Provincial Health Commission(Proteomics Shanxi studio for Huanghe professor)
- Fundamental Research Program of Shanxi Province(No.202303021221192); 2023 COVID-19 Emergency Project of Shanxi Health Commission (Nos.2023XG001,2023XG005)
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Affiliation(s)
- Jiali Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
| | - Weiwei Tian
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xiansheng Liu
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Liping Yang
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China.
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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14
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Zhang T, Ren C, Yang Z, Zhang N, Tang H. Exploration of the role of immune cells and cell therapy in hepatocellular carcinoma. Front Immunol 2025; 16:1569150. [PMID: 40308592 PMCID: PMC12040661 DOI: 10.3389/fimmu.2025.1569150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Hepatocellular carcinoma stands as one of the foremost contributors to cancer-associated fatalities globally, and the limitations of traditional treatment methods have prompted researchers to explore new therapeutic options. Recently, cell therapy has emerged as a promising approach for HCC, showing significant potential in improving patient outcomes. This review article explores the use of cell therapy for HCC, covering different types, the mechanisms behind their effectiveness, recent advancements in clinical trials, and ongoing challenges. This article aims to provide insightful perspectives for future research and clinical applications in treating HCC by synthesizing current knowledge.
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Affiliation(s)
- Tao Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Cong Ren
- The Second Clinical College, Chongqing Medical University, Chongqing, China
| | - Zhanyu Yang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ning Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Haowen Tang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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15
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Shenoy A, Yousif A, Hussain MD. Recent Advances and Challenges in the Treatment of Advanced Pancreatic Cancer: An Update on Completed and Ongoing Clinical Trials. Cancers (Basel) 2025; 17:1319. [PMID: 40282495 PMCID: PMC12025738 DOI: 10.3390/cancers17081319] [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: 02/20/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/29/2025] Open
Abstract
Pancreatic cancer is a deadly disease with a low survival rate, particularly in its advanced stages. Advanced pancreatic cancer remains a major clinical challenge due to limited treatment options. Surgical resection may not always be feasible, and traditional chemotherapy often shows restricted effectiveness. As a result, researchers are exploring a multifaceted therapeutic approach targeting the genetic and molecular drivers of the disease. A combination of molecular profiling and targeted therapies are being investigated to improve outcomes and address the shortcomings of traditional treatments. The focus of this review is to provide a summary of current and completed clinical trials for the treatment of advanced pancreatic cancer. This includes adagrasib (a KRAS inhibitor), olaparib (a PARP inhibitor for BRCA mutations), APG-1387 (an IAP antagonist), minnelide (an anti-stromal agent), arimastat (an MMP inhibitor), MK-0646 (an IGF1R inhibitor), sirolimus (an mTOR inhibitor), and metabolic inhibitors. These agents are being evaluated both as standalone treatments and in combination with standard therapy. Furthermore, we have summarized novel approaches such as cancer vaccines and ablation techniques as emerging strategies in the treatment of advanced pancreatic cancer. We have also examined the challenges in treating advanced pancreatic cancer and the factors contributing to therapeutic failure, which may offer valuable insights for developing more effective treatment strategies and innovative drug designs.
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Affiliation(s)
- Abhinav Shenoy
- College of Engineering, Texas A&M University, College Station, TX 77843, USA;
| | - Amar Yousif
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;
| | - Muhammad Delwar Hussain
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;
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16
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Moazzeni A, Kheirandish M, Khamisipour G, Rahbarizadeh F, Pourfathollah AA. Leukoreduction filter derived NK cells offer a promising source for off the shelf CAR NK cell immunotherapy. Sci Rep 2025; 15:12755. [PMID: 40223011 PMCID: PMC11994799 DOI: 10.1038/s41598-025-97584-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/07/2025] [Indexed: 04/15/2025] Open
Abstract
Immunotherapy employing natural killer (NK) cells has emerged as a transformative approach to treating hematological malignancies. The reprogramming of NK cells by incorporating a chimeric antigen receptor (CAR) equipped with potent signaling domains has demonstrated efficacy in enhancing NK cell responses and improving specificity in recognizing cancerous cells. Despite these advancements, the primary challenge in implementing allogeneic NK cell therapy requiring a viable donor source for clinically relevant doses remains unresolved. This study tested NK cells obtained from leukoreduction filters (LRF) post-blood donation to address the need for an efficient and scalable supply of NK cells for generating anti-BCMA CAR NK cells. LRF-NK cells were isolated under sterile conditions and compared with peripheral blood (PB)-derived NK cells in terms of immunophenotype, proliferation capacity, and functional characteristics. Notably, no significant differences in inherent characteristics were observed between LRF-NK and PB-NK cells. Subsequently, both NK cell populations were employed to generate anti-BCMA CAR-NK cells. The data revealed a high specific cytotoxicity of Anti-BCMA CAR LRF-NK cells during co-culture with U266-B1 cells (70.3 ± 4.78%), surpassing that observed with CCRF-CEM cells (31.3 ± 2.35%) and similar to Anti-BCMA CAR PB-NK cells. Furthermore, the expression of IFN-γ and Granzyme B, following the co-culture of Anti-BCMA CAR LRF-NK cells with target cells, mirrored that observed in Anti-BCMA CAR PB-NK cells. This study provides the rationale and feasibility of utilizing LRF-NK cells as a safe, high-yield, accessible, and optimal cost-effective source for cancer immunotherapy.
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Affiliation(s)
- Ali Moazzeni
- Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Hemmat Highway Next to Milad Tower, P.O. Box: 14665-1157, Tehran, Iran
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, P.O. Box: 7518759577, Bushehr, Iran
| | - Maryam Kheirandish
- Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Hemmat Highway Next to Milad Tower, P.O. Box: 14665-1157, Tehran, Iran.
| | - Gholamreza Khamisipour
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, P.O. Box: 7518759577, Bushehr, Iran.
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Akbar Pourfathollah
- Immunology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Iranian Blood Transfusion Organization, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Chen L, Yin J, Xu K, Cui Y, Zhu S, Li T, Lv T, Song Y, Zhan P. Novel bioengineered drugs with immunotherapies for malignant pleural effusion: Remodulate tumor immune microenvironment and activate immune system. Crit Rev Oncol Hematol 2025; 211:104717. [PMID: 40194717 DOI: 10.1016/j.critrevonc.2025.104717] [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: 02/19/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/09/2025] Open
Abstract
Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.
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Affiliation(s)
- Lu Chen
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jie Yin
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ke Xu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - YuTing Cui
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - SuHua Zhu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China.
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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18
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Mutlu S, Fytianos K, Ferrié C, Scalise M, Mykoniati S, Gazdhar A, Blank F. Adoptive Transfer of T Cells as a Potential Therapeutic Approach in the Bleomycin-Injured Mouse Lung. J Gene Med 2025; 27:e70018. [PMID: 40159455 PMCID: PMC11955259 DOI: 10.1002/jgm.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/21/2025] [Accepted: 03/15/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unknown etiology and complex pathophysiology that are not fully understood. The disease involves intricate cellular interplay, particularly among various immune cells. Currently, there is no treatment capable of reversing the fibrotic process or aiding lung regeneration. Hepatocyte growth factor (HGF) has demonstrated antifibrotic properties, whereas the adoptive transfer of modified T cells is a well-established treatment for various malignancies. We aimed to understand the dynamics of T cells in the progression of lung fibrosis and to study the therapeutic benefit of adoptive T cell transfer in a bleomycin-injured mouse lung (BLM) model. METHODS T cells were isolated from the spleen of naïve mice and transfected in vitro with mouse HGF plasmid and were administered intratracheally to the mice lungs 7 days post-bleomycin injury to the lung. Lung tissue and bronchoalveolar lavage were collected and analyzed using flow cytometry, histology, qRT-PCR, ELISA, and hydroxyproline assay. RESULTS Our findings demonstrate the successful T cell therapy of bleomycin-induced lung injury through the adoptive transfer of HGF-transfected T cells in mice. This treatment resulted in decreased collagen deposition and a balancing of immune cell exhaustion and cytokine homeostasis compared with untreated controls. In vitro testing showed enhanced apoptosis in myofibroblasts induced by HGF-overexpressing T cells. CONCLUSIONS Taken together, our data highlight the great potential of adoptive T cell transfer as an emerging therapy to counteract lung fibrosis.
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Affiliation(s)
- Seyran Mutlu
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of BernBernSwitzerland
| | - Kleanthis Fytianos
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
| | - Céline Ferrié
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
| | - Melanie Scalise
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
| | | | - Amiq Gazdhar
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
| | - Fabian Blank
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR)University of BernBernSwitzerland
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19
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Bragasin EI, Cheng J, Ford L, Poei D, Ali S, Hsu R. Advances in adoptive cell therapies in small cell lung cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002302. [PMID: 40160238 PMCID: PMC11949692 DOI: 10.37349/etat.2025.1002302] [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: 11/18/2024] [Accepted: 02/10/2025] [Indexed: 04/02/2025] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive tumor characterized by early metastasis and resistance to treatment, making it a prime target for therapeutic investigation. The current standard of care for frontline treatment involves a combination of chemotherapeutic agents and immune checkpoint inhibitors (ICIs), though durability of response remains limited. The genetic heterogeneity of SCLC also complicates the development of new therapeutic options. Adoptive cell therapies show promise by targeting specific mutations in order to increase efficacy and minimize toxicity. There has been significant investigation in three therapeutic classes for application towards SCLC: antibody drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR)-T cell therapies. This review summarizes the recent advances and challenges in the development of adoptive cell therapies. Genetic targets such as delta-like ligand 3 (DLL3), trophoblast cell surface antigen 2 (Trop2), B7-H3 (CD276), gangliosides disialoganglioside GD2 (GD2) and ganglioside GM2 (GM2) have been found to be expressed in SCLC, which makes them prime targets for therapy development. While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC.
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Affiliation(s)
- Eljie Isaak Bragasin
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Justin Cheng
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Lauren Ford
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Darin Poei
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Sana Ali
- Department of Medicine, Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Robert Hsu
- Department of Medicine, Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
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20
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Han X, Zhang J, Li W, Huang X, Wang X, Wang B, Gao L, Chen H. The role of B2M in cancer immunotherapy resistance: function, resistance mechanism, and reversal strategies. Front Immunol 2025; 16:1512509. [PMID: 40191187 PMCID: PMC11968357 DOI: 10.3389/fimmu.2025.1512509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Immunotherapy has emerged as a preeminent force in the domain of cancer therapeutics and achieved remarkable breakthroughs. Nevertheless, the high resistance has become the most substantial impediment restricting its clinical efficacy. Beta-2 microglobulin (B2M), the light chain of major histocompatibility complex (MHC) class I, plays an indispensable part by presenting tumor antigens to cytotoxic T lymphocytes (CTLs) for exerting anti-tumor effects. Accumulating evidence indicates that B2M mutation/defect is one of the key mechanisms underlying tumor immunotherapy resistance. Therefore, elucidating the role played by B2M and devising effective strategies to battle against resistance are pressing issues. This review will systematically expound upon them, aiming to provide insight into the potential of B2M as a promising target in anticancer immune response.
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Affiliation(s)
- Xiaowen Han
- Lanzhou University Second Hospital, Lanzhou, China
| | - Jiayi Zhang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Weidong Li
- Lanzhou University Second Hospital, Lanzhou, China
| | | | - Xueyan Wang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Bofang Wang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, China
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Wong ET, Cielo D, Svokos K, Doberstein C, Sampath P, Donahue JE, Punsoni M, Rodrigues N, Rothell F, Edwards R, Wang E, Riccelli T, Chuck C, Shaaya EA, Sastry R, Ali R, Shao B, Abdulrazeq H, Sun FW, Feler J, Santos Fontánez SE, Nieves NA, Dobertsein C, Dailey J, Yu C, Sarangi S, Elinzano H, Boxerman JL, Yu E, Safran H, Seyhan AA, El-Deiry WS, Keith S, Gokaslan ZL, Chen CC, Malik A. IGV-001 cellular immunotherapy for newly diagnosed glioblastoma: overcoming the logistic challenge. Front Oncol 2025; 15:1556450. [PMID: 40171253 PMCID: PMC11959700 DOI: 10.3389/fonc.2025.1556450] [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: 01/06/2025] [Accepted: 02/14/2025] [Indexed: 04/03/2025] Open
Abstract
Background IGV-001 is a type of cellular immunotherapy currently being investigated for treating glioblastoma (NCT04485949). It uses the patient's tumor to elicit an autologous immune response. Methods The process involves (i) craniotomy for maximum safe resection of the glioblastoma, (ii) ex-vivo treatment of the tumor with an anti-sense oligodeoxynucleotide against insulin-like growth factor 1 receptor followed by irradiation, (iii) placement of the treated tumor in multiple bio-diffusion chambers, which are implanted into the patient's abdominal sheath to elicit an immune response, and (iv) explantation of the chambers 48 hours later. The clinical trial was open at 32 sites in the United States, and eligible subjects were randomized in a 2:1 ratio to receive bio-diffusion chambers containing either conditioned glioblastoma tissue or a placebo. Patients subsequently proceeded to standard-of-care treatment with concomitant radiation-temozolomide, followed by 6 cycles of adjuvant temozolomide. Results The execution of the IGV-001 protocol procedure is complicated and involves a multi-step process requiring mobilization of multiple services within the cancer center of a tertiary care hospital, including neurosurgery, neuro-oncology, radiation oncology, neuroradiology, cancer clinical trial office, and operating room personnel to fulfill the pre-specified protocol requirements in a timely fashion. Conclusions We have learned a great deal in the process of developing and executing our internal procedures for this clinical trial. Our description of the IGV-001 protocol workflow may serve as a "blueprint" for future implementation of this type of cellular immunotherapy at other centers. We further discuss some of the lessons we have learned during the trial.
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Affiliation(s)
- Eric T. Wong
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Department of Neurology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Department of Radiation Oncology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Legorreta Cancer Center at Brown University, Providence, RI, United States
| | - Deus Cielo
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Konstantina Svokos
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Curt Doberstein
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Prakash Sampath
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - John E. Donahue
- Division of Neuropathology, Department of Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Michael Punsoni
- Division of Neuropathology, Department of Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Nuno Rodrigues
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Francesca Rothell
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Robert Edwards
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Elaina Wang
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Tori Riccelli
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Carlin Chuck
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Elias A. Shaaya
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Rahul Sastry
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Rohaid Ali
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Belinda Shao
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Hael Abdulrazeq
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Felicia W. Sun
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Joshua Feler
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Santos E. Santos Fontánez
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Natalie Amaral Nieves
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Cody Dobertsein
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Jennifer Dailey
- Division of Neuropathology, Department of Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Christine Yu
- Division of Neuropathology, Department of Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Sasmit Sarangi
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Department of Neurology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Heinrich Elinzano
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Department of Neurology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Jerrold L. Boxerman
- Department of Diagnostic Imaging, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Esther Yu
- Department of Radiation Oncology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Howard Safran
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Legorreta Cancer Center at Brown University, Providence, RI, United States
| | - Attila A. Seyhan
- Legorreta Cancer Center at Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Wafik S. El-Deiry
- Division of Hematology/Oncology, Department of Medicine and Brown University Health Cancer Institute, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Legorreta Cancer Center at Brown University, Providence, RI, United States
| | - Sharonda Keith
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Ziya L. Gokaslan
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Clark C. Chen
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
- Legorreta Cancer Center at Brown University, Providence, RI, United States
| | - Athar Malik
- Department of Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, United States
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Song P, Pan G, Zhang Y, Ni Y, Wang Q, Shi J, Peng Y, Jing R, Luo D. Prospects and Challenges of Immunotherapy for Thyroid Cancer. Endocr Pract 2025; 31:373-379. [PMID: 39631664 DOI: 10.1016/j.eprac.2024.11.012] [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: 08/16/2024] [Revised: 10/21/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Thyroid cancer generally boasts a favorable prognosis; however, advanced and refractory cases exhibit aggressive characteristics and resistance to conventional therapies, necessitating the investigation of innovative treatment modalities. Immunotherapy, which harnesses the body's immune system to target cancer cells, has shown considerable promise for specific thyroid cancer subtypes. OBJECTIVE This review article aims to encapsulate the latest advancements in immunotherapy for thyroid cancer, examining its mechanisms, therapeutic efficacy, ongoing challenges, and the potential benefits of combination therapy approaches. METHODS An extensive literature review and critical analysis of clinical trial data were conducted to inform this synthesis. RESULTS The review reveals that immunotherapy strategies, encompassing immune checkpoint inhibitors, CAR-T cell therapy, tumor vaccines, and immunomodulators, are demonstrating efficacy in the treatment of thyroid cancer. Notably, checkpoint inhibitors have been particularly effective in anaplastic and poorly differentiated thyroid cancers, albeit with challenges such as treatment resistance and adverse effects. The application of CAR-T cell therapy, successful in hematologic cancers, provides a novel perspective for thyroid cancer treatment, although its efficacy in solid tumors requires further study. Additionally, research into tumor vaccines and immunomodulators is advancing, with preliminary evidence suggesting their therapeutic potential for thyroid cancer patients. CONCLUSION The recognition of the immune microenvironment's role in treatment responsiveness is pivotal for enhancing the care of thyroid cancer patients. This review underscores the significance of combination therapy as a means to optimize treatment outcomes and charts a course for future research endeavors to broaden the spectrum of effective treatment options available to thyroid cancer patients.
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Affiliation(s)
- Ping Song
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Gang Pan
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yu Zhang
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yeqin Ni
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Qianyu Wang
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jingjng Shi
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - You Peng
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Ruirui Jing
- Department of Translational Medicine and Clinical Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Dingcun Luo
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China; The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; College of Mathematical Medicine, Zhejiang Normal University, Jinhua, Zhejiang, China.
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Bloom M, Podder S, Dang H, Lin D. Advances in Immunotherapy in Hepatocellular Carcinoma. Int J Mol Sci 2025; 26:1936. [PMID: 40076561 PMCID: PMC11900920 DOI: 10.3390/ijms26051936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/10/2025] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.
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Affiliation(s)
- Matthew Bloom
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Sourav Podder
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (S.P.); (H.D.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (S.P.); (H.D.)
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
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Khorasanchi A, Hong F, Yang Y, Singer EA, Wang P, Li M, Zheng L, Monk P, Mortazavi A, Meng L. Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:9. [PMID: 40051495 PMCID: PMC11883235 DOI: 10.20517/cdr.2024.173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 03/09/2025]
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers a uniquely comprehensive and integrative perspective on these resistance pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid receptor signaling, splice variants, post-translational modifications, altered coregulators, and intratumoral hormone biosynthesis) and AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, and alternative growth factor signaling). We also highlight resistance mechanisms influencing immunotherapy, chemotherapy, radiopharmaceutical therapy and targeted therapy. By synthesizing emerging insights across these domains, this review not only clarifies the underlying biology of mCRPC resistance but also identifies key leverage points for more effective interventions. Building on this foundation, we propose a forward-looking framework for overcoming mCRPC drug resistance, emphasizing the importance of biomarker-guided patient selection, combination strategies that simultaneously target multiple resistance mechanisms, and novel therapies under investigation. These recommendations are intended to guide future clinical trial designs and research priorities that move beyond incremental improvements. Ultimately, this comprehensive synthesis aims to serve as a resource for clinicians and researchers to accelerate the development of durable, precision-based treatment strategies in mCRPC.
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Affiliation(s)
- Adam Khorasanchi
- Division of Hospital Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Feng Hong
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Yuanquan Yang
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Eric A. Singer
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Peng Wang
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Mingjia Li
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Linghua Zheng
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Paul Monk
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Amir Mortazavi
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Lingbin Meng
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Mehta A, Motavaf M, Nebo I, Luyten S, Osei-Opare KD, Gru AA. Advancements in Melanoma Treatment: A Review of PD-1 Inhibitors, T-VEC, mRNA Vaccines, and Tumor-Infiltrating Lymphocyte Therapy in an Evolving Landscape of Immunotherapy. J Clin Med 2025; 14:1200. [PMID: 40004731 PMCID: PMC11856346 DOI: 10.3390/jcm14041200] [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: 01/16/2025] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna's mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient's tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.
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Affiliation(s)
- Apoorva Mehta
- Columbia University Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA; (I.N.); (S.L.); (K.D.O.-O.)
| | - Mateen Motavaf
- Duke University School of Medicine, Durham, NC 27710, USA;
| | - Ikenna Nebo
- Columbia University Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA; (I.N.); (S.L.); (K.D.O.-O.)
| | - Sophia Luyten
- Columbia University Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA; (I.N.); (S.L.); (K.D.O.-O.)
| | - Kofi D. Osei-Opare
- Columbia University Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA; (I.N.); (S.L.); (K.D.O.-O.)
| | - Alejandro A. Gru
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY 10032, USA;
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Li M, Chen T, Huang R, Cen Y, Zhao F, Fan R, He G. Chimeric antigen receptor-T cells targeting AFP-GPC3 mediate increased antitumor efficacy in hepatocellular carcinoma. Arab J Gastroenterol 2025; 26:84-93. [PMID: 39757079 DOI: 10.1016/j.ajg.2024.12.002] [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: 07/02/2024] [Revised: 11/07/2024] [Accepted: 12/07/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND AND STUDY AIMS As a novel immunotherapy, chimeric antigen receptor T (CAR-T) cell technology is successful in treating hematologic malignancies, and exhibits potential benefits in partial solid tumors. Therapies targeting one antigen have some weaknesses, and dual-targeted CAR-T cells may be a better option. Alpha-fetoprotein (AFP) and glypican-3 (GPC3) are both highly expressed in hepatocellular carcinoma (HCC) and serve as important markers. Our study aimed to compare the cytotoxicity effect of AFP and GPC3 dual-targeted CAR-T cells on HCC cells in vitro and its therapeutic effects on a SCID xenograft model with those of single-targeted CAR-T cells. MATERIALS AND METHODS pLVX lentivirus vectors loaded with AFP CAR, GPC3 CAR, or AFP-GPC3 CAR constructs were transfected into human T lymphocytes. Control T, AFP CAR-T, GPC3 CAR-T, and AFP-GPC3 CAR-T cells were used as effector cells, and HLE (AFP-GPC3-), Sh-GPC3-Huh-7 (AFP+), Sh-AFP-Huh-7 (GPC3+), and Huh-7 (AFP+GPC3+) cells were used as target cells. After their co-culture for 6 h, the LDH cytotoxicity assay was employed to estimate the cell-killing effects of CAR-T cells on the target HCC cells. SCID mice bearing Huh-7 cell-derived neoplasms were injected with CAR-T cells, after which the pathological changes, CD3ζ expression, and IL-2 and IFN-γ levels in mouse tumor tissues were determined. RESULTS AFP and GPC3 were highly expressed in Huh-7 cells. AFP-GPC3 CAR-T cells exerted significant cell-killing effects on the HCC cells that expressed specific targeting antigen molecules (AFP and GPC3). Besides, AFP-GPC3 CAR-T cells better promoted Th cytokine secretion by Huh-7 cells than AFP CAR-T and GPC3 CAR-T cells. In vivo results suggested that AFP-GPC3 CAR-T cells better inhibited the growth of Huh-7 cell (AFP+GPC3+)-derived neoplasms than AFP CAR-T and GPC3 CAR-T cells. CONCLUSION AFP and GPC3 dual-targeted CAR-T cells showed better anti-tumor effects in HCC than AFP or GPC3 single-targeted CAR-T cells.
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Affiliation(s)
- Mingxing Li
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China
| | - Tailin Chen
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China
| | - Rongshi Huang
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China.
| | - Yanhui Cen
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China.
| | - Feilan Zhao
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China
| | - Rong Fan
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China
| | - Guozhen He
- Embryo Formation Teaching and Research Section, Guangxi University of Chinese Medicine, No.13 Wuhe Avenue, Nanning 530200, Guangxi, China
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Ascari S, Chen R, Vivaldi C, Stefanini B, De Sinno A, Dalbeni A, Federico P, Tovoli F. Advancements in immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2025; 25:151-165. [PMID: 39913170 DOI: 10.1080/14737140.2025.2461631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The advent of immune-based combinations, primarily leveraging immune checkpoint inhibitors, has revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). The current scenario features multiple therapies that have shown superiority over tyrosine kinase inhibitors; however, the absence of direct comparisons and validated prognostic biomarkers complicates therapeutic decision-making. Additionally, a significant proportion of patients still exhibit primary or secondary resistance to existing immunotherapies, underscoring the ongoing need for novel therapeutic strategies. AREAS COVERED This narrative review discusses current strategies aimed at improving the efficacy of immunotherapy for HCC, focusing on the following aspects: available therapeutic options, identification of prognostic biomarkers, approaches to overcoming resistance (including the development of neoantigen vaccines), and the exploration of adjuvant and neoadjuvant strategies. EXPERT OPINION The future of systemic therapies for HCC is likely to be driven by advancements in immunotherapy. Key areas of exploration for the coming years include the discovery of novel checkpoint inhibitors or complementary agents to enhance tumor response when combined with existing treatments, a shift toward neoadjuvant/perioperative trials instead of traditional adjuvant approaches, and the development of personalized neoantigen vaccines.
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Affiliation(s)
- Sara Ascari
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rusi Chen
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea De Sinno
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Dalbeni
- Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
- Unit of General Medicine C, Medicine Department, University of Verona and Hospital Trust (AOUI) of Verona, Verona, Italy
| | | | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Boomgarden AC, Upadhyay C. Progress and Challenges in HIV-1 Vaccine Research: A Comprehensive Overview. Vaccines (Basel) 2025; 13:148. [PMID: 40006695 PMCID: PMC11860913 DOI: 10.3390/vaccines13020148] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/20/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
The development of an effective HIV-1 vaccine remains a formidable challenge in biomedical research. Despite significant advancements in our understanding of HIV biology and pathogenesis, progress has been impeded by factors such as the virus's genetic diversity, high mutation rates, and its ability to establish latent reservoirs. Recent innovative approaches, including mosaic vaccines and mRNA technology to induce broadly neutralizing antibodies, have shown promise. However, the efficacy of these vaccines has been modest, with the best results achieving approximately 30% effectiveness. Ongoing research emphasizes the necessity of a multifaceted strategy to overcome these obstacles and achieve a breakthrough in HIV-1 vaccine development. This review summarizes current approaches utilized to further understand HIV-1 biology and to create a global vaccine. We discuss the impact of these approaches on vaccine development for other diseases, including COVID-19, influenza, and Zika virus. Additionally, we highlight the specific limitations faced with each approach and present the methods researchers employ to overcome these challenges. These innovative techniques, which have demonstrated preclinical and clinical success, have advanced the field closer to the ultimate goal of developing a global HIV-1 vaccine. Leveraging these advancements will enable significant strides in combating HIV-1 and other infectious diseases, ultimately improving global health outcomes.
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Affiliation(s)
| | - Chitra Upadhyay
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
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Hu Q, Xuan J, Wang L, Shen K, Gao Z, Zhou Y, Wei C, Gu J. Application of adoptive cell therapy in malignant melanoma. J Transl Med 2025; 23:102. [PMID: 39844295 PMCID: PMC11752767 DOI: 10.1186/s12967-025-06093-2] [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: 11/05/2024] [Accepted: 01/07/2025] [Indexed: 01/24/2025] Open
Abstract
Cutaneous melanoma is one of the most aggressive skin cancers originating from skin pigment cells. Patients with advanced melanoma suffer a poor prognosis and generally cannot benefit well from surgical resection and chemo/target therapy due to metastasis and drug resistance. Thus, adoptive cell therapy (ACT), employing immune cells with specific tumor-recognizing receptors, has emerged as a promising therapeutic approach to display on-tumor toxicity. This review discusses the application, efficacy, limitations, as well as future prospects of four commonly utilized approaches -including tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR) T cell, engineered T-cell receptor T cells, and chimeric antigen receptor NK cells- in the context of malignant melanoma.
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Affiliation(s)
- Qianrong Hu
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jiangying Xuan
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Lu Wang
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Kangjie Shen
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zixu Gao
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yuhong Zhou
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Chuanyuan Wei
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Jianying Gu
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
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Matthews AJ, Starkie FE, Staniaszek LE, Kane NM. The Role of Electroencephalography Following CAR-T Cell Therapy in Clinical Practice. Clin EEG Neurosci 2025:15500594241312451. [PMID: 39773224 DOI: 10.1177/15500594241312451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Objectives:Neurotoxicity, encephalopathy, and seizures can occur following chimeric antigen receptor (CAR)-T cell therapy. Our aim was to assess what value electroencephalography (EEG) offers for people undergoing CAR-T treatment in clinical practice, including possible diagnostic, management, and prognostic roles. Methods: All patients developing CAR-T related neurotoxicity referred for EEG were eligible for inclusion. Reasons for EEG referral and qualitative EEG findings were analysed and reported. The relationship between objective quantitative EEG (QEEG) encephalopathy grade and clinical neurotoxicity (immune effector cell-associated neurotoxicity syndrome; ICANS) grade was determined. The prognostic ability of QEEG grade was assessed for survival and functional status. Results: Twenty-eight patients with 53 EEG recordings were included. Common reasons given on EEG referrals were possible seizure diagnosis (n = 38), reduced consciousness (n = 8), and superimposed cerebral infection (n = 4). Four focal seizures were detected on three (3/53; 5.7%) EEGs. There was a moderately positive correlation between QEEG grade and ICANS grade (r = + 0.41, p = .030). QEEG grade could not predict survival at 3 months (Area Under Curve; AUC = 0.673) or 6 months (AUC = 0.578), nor could it predict functional status at 1 month (r = + 0.40; p = .080), 3 months (r = + 0.19; p = .439), or time to return to baseline (r = + 0.32; p = .156). Conclusions: EEG was useful in seizure diagnosis. QEEG has a possible role as a specific biomarker of encephalopathy/neurotoxicity. EEG generated no tangible changes in patient management. QEEG was unable to prognosticate survival or functional status.
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Affiliation(s)
- Alexander J Matthews
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
| | - Fiona E Starkie
- Bristol Haematology and Oncology Centre, University Hospitals Bristol and Weston NHS Foundation Trust, Horfield Road, Bristol, BS2 8ED, UK
| | - Lydia E Staniaszek
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
| | - Nicholas M Kane
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
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Marei HE, Bedair K, Hasan A, Al-Mansoori L, Caratelli S, Sconocchia G, Gaiba A, Cenciarelli C. Current status and innovative developments of CAR-T-cell therapy for the treatment of breast cancer. Cancer Cell Int 2025; 25:3. [PMID: 39755633 PMCID: PMC11700463 DOI: 10.1186/s12935-024-03615-8] [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: 07/15/2024] [Accepted: 12/12/2024] [Indexed: 01/06/2025] Open
Abstract
Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Khaled Bedair
- Department of Social Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Layla Al-Mansoori
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Sara Caratelli
- Institute of Translational Pharmacology-CNR, Rome, Italy
| | | | - Alice Gaiba
- Institute of Translational Pharmacology-CNR, Rome, Italy
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Hosseini SA, Nasab NK, Kargozar S, Wang AZ. Advanced biomaterials and scaffolds for cancer immunotherapy. BIOMATERIALS FOR PRECISION CANCER MEDICINE 2025:377-424. [DOI: 10.1016/b978-0-323-85661-4.00016-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Zhang Q, He J, Zhu D, Chen Y, Fu M, Lu S, Qiu Y, Zhou G, Yang G, Jiang Z. Genetically modified organoids for tissue engineering and regenerative medicine. Adv Colloid Interface Sci 2025; 335:103337. [PMID: 39547125 DOI: 10.1016/j.cis.2024.103337] [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: 01/18/2024] [Revised: 07/23/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
To date, genetically modified organoids are emerging as a promising 3D modeling tool aimed at solving genetically relevant clinical and biomedical problems for regenerative medicine and tissue engineering. As an optimal vehicle for gene delivery, genetically modified organoids can enhance or reduce the expression of target genes through virus and non-virus-based gene transfection methods to achieve tissue regeneration. Animal experiments and preclinical studies have demonstrated the beneficial role of genetically modified organoids in various aspects of organ regeneration, including thymus, lacrimal glands, brain, lung, kidney, photoreceptors, etc. Furthermore, the technology offers a potential treatment option for various diseases, such as Fabry disease, non-alcoholic steatohepatitis, and Lynch syndrome. Nevertheless, the uncertain safety of genetic modification, the risk of organoid application, and bionics of current genetically modified organoids are still challenging. This review summarizes the researches on genetically modified organoids in recent years, and describes the transfection methods and functions of genetically modified organoids, then introduced their applications at length. Also, the limitations and future development directions of genetically modified organoids are included.
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Affiliation(s)
- Qinmeng Zhang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Jin He
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Danji Zhu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Yunxuan Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Mengdie Fu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Shifan Lu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Yuesheng Qiu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Guodong Zhou
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
| | - Zhiwei Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
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Ward MB, Jones AB, Krenciute G. Therapeutic advantage of combinatorial chimeric antigen receptor T cell and chemotherapies. Pharmacol Rev 2025; 77:100011. [PMID: 39952691 DOI: 10.1124/pharmrev.124.001070] [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: 04/23/2024] [Revised: 08/28/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for treatment of solid and brain tumors has been met with many challenges, including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across patients with cancer. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this because chemotherapeutics could augment CAR T cells for improved antitumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts toward achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics because these will be more easily translated to the clinic but also review nonapproved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Overall, this review highlights the promise of CAR T cell and chemotherapy combinations with a specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for patients with cancer. SIGNIFICANCE STATEMENT: Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts toward studying CAR T and chemotherapy combinatorial therapies and offer perspectives on optimal ways to identify new and effective combinations moving forward.
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Affiliation(s)
- Meghan B Ward
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Amber B Jones
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Giedre Krenciute
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Liu Y, Zhou F, Ali H, Lathia JD, Chen P. Immunotherapy for glioblastoma: current state, challenges, and future perspectives. Cell Mol Immunol 2024; 21:1354-1375. [PMID: 39406966 PMCID: PMC11607068 DOI: 10.1038/s41423-024-01226-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.
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Affiliation(s)
- Yang Liu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Fei Zhou
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Heba Ali
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44195, USA
| | - Peiwen Chen
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, 44195, USA.
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Geils C, Kathrein K. Augmentation of Solid Tumor Immunotherapy With IL-12. J Gene Med 2024; 26:e70000. [PMID: 39618102 PMCID: PMC11609498 DOI: 10.1002/jgm.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/15/2024] [Accepted: 11/01/2024] [Indexed: 12/13/2024] Open
Abstract
Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically "cold" to "hot." Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.
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Affiliation(s)
- Christian Geils
- Department of Biological SciencesUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Katie L. Kathrein
- Department of Biological SciencesUniversity of South CarolinaColumbiaSouth CarolinaUSA
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Bartoli-Leonard F, Pennel T, Caputo M. Immunotherapy in the Context of Aortic Valve Diseases. Cardiovasc Drugs Ther 2024; 38:1173-1185. [PMID: 39017904 PMCID: PMC11680629 DOI: 10.1007/s10557-024-07608-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/08/2024] [Indexed: 07/18/2024]
Abstract
PURPOSE Aortic valve disease (AVD) affects millions of people around the world, with no pharmacological intervention available. Widely considered a multi-faceted disease comprising both regurgitative pathogenesis, in which retrograde blood flows back through to the left ventricle, and aortic valve stenosis, which is characterized by the thickening, fibrosis, and subsequent mineralization of the aortic valve leaflets, limiting the anterograde flow through the valve, surgical intervention is still the main treatment, which incurs considerable risk to the patient. RESULTS Though originally thought of as a passive degeneration of the valve or a congenital malformation that has occurred before birth, the paradigm of AVD is shifting, and research into the inflammatory drivers of valve disease as a potential mechanism to modulate the pathobiology of this life-limiting pathology is taking center stage. Following limited success in mainstay therapeutics such as statins and mineralisation inhibitors, immunomodulatory strategies are being developed. Immune cell therapy has begun to be adopted in the cancer field, in which T cells (chimeric antigen receptor (CAR) T cells) are isolated from the patient, programmed to attack the cancer, and then re-administered to the patient. Within cardiac research, a novel T cell-based therapeutic approach has been developed to target lipid nanoparticles responsible for increasing cardiac fibrosis in a failing heart. With clonally expanded T-cell populations recently identified within the diseased valve, their unique epitope presentation may serve to identify novel targets for the treatment of valve disease. CONCLUSION Taken together, targeted T-cell therapy may hold promise as a therapeutic platform to target a multitude of diseases with an autoimmune aspect, and this review aims to frame this in the context of cardiovascular disease, delineating what is currently known in the field, both clinically and translationally.
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Affiliation(s)
- Francesca Bartoli-Leonard
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK.
- Bristol Heart Institute, University Hospital Bristol and Weston NHS Foundation Trust, Bristol, UK.
- Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Cape Town, South Africa.
| | - Tim Pennel
- Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Cape Town, South Africa
| | - Massimo Caputo
- Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK
- Bristol Heart Institute, University Hospital Bristol and Weston NHS Foundation Trust, Bristol, UK
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Sharma SD, Leung SH, Viatte S. Genetics of rheumatoid arthritis. Best Pract Res Clin Rheumatol 2024; 38:101968. [PMID: 38955657 DOI: 10.1016/j.berh.2024.101968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/17/2024] [Accepted: 06/24/2024] [Indexed: 07/04/2024]
Abstract
In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.
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Affiliation(s)
- Seema D Sharma
- Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Centre, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
| | - Shek H Leung
- Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
| | - Sebastien Viatte
- Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Centre, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
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Zhao Y, Tan M, Yin Y, Zhang J, Song Y, Li H, Yan L, Jin Y, Wu Z, Yang T, Jiang T, Li H. Comprehensive macro and micro views on immune cells in ischemic heart disease. Cell Prolif 2024; 57:e13725. [PMID: 39087342 PMCID: PMC11628753 DOI: 10.1111/cpr.13725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 06/25/2024] [Accepted: 07/18/2024] [Indexed: 08/02/2024] Open
Abstract
Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.
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Affiliation(s)
- Yongjian Zhao
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Mingyue Tan
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Department of Geriatrics, Southwest HospitalThe Third Military Medical University (Army Medical University)ChongqingChina
| | - Yunfei Yin
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Jun Zhang
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Yiyi Song
- Suzhou Medical College of Soochow UniversityJiangsuChina
| | - Hang Li
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Lin Yan
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Yifeng Jin
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Ziyue Wu
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Tianke Yang
- Department of Ophthalmology, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiChina
| | - Tingbo Jiang
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Hongxia Li
- Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
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Zhang W, Wei W, Ma L, Du H, Jin A, Luo J, Li X. Mapping the landscape: a bibliometric study of global chimeric antigen receptor T cell immunotherapy research. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9227-9241. [PMID: 38953967 DOI: 10.1007/s00210-024-03258-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/23/2024] [Indexed: 07/04/2024]
Abstract
The rise of immunotherapy provided new approaches to cancer treatment. We aimed to describe the contribution of chimeric antigen receptor T cell immunotherapy to future prospects. We analyzed 8035 articles from the Web of Science Core Collection with CiteSpace that covered with various aspects with countries, institutions, authors, co-cited authors, journals, keywords, and references. The USA was the most prolific country, with the University of Pennsylvania being the most published institution. Among individual authors, June Carl H published the most articles, while Maude SL was the most frequently co-cited author. "Blood" emerged as the most cited journal. Keyword clustering revealed six core themes: "Expression," "Chimeric Antigen Receptor," "Tumor Microenvironment," "Blinatumomab," "Multiple Myeloma," and "Cytokine Release Syndrome." In the process of researching the timeline chart of keywords and references, "Large B-cell lymphoma" was located on the right side of the timeline. In the keyword prominence analysis, we found that the keywords "biomarkers," "pd-1," "antibody drug conjugate," "BCMA," and "chimeric antigen" had high explosive intensity in the recent past. We found that in terms of related diseases, "large B-cell lymphoma" and "cytokine release syndrome" are still difficult problems in the future. In the study of therapeutic methods, "BCMA," "PD-1," "chimeric antigen," and "antibody drug conjugate" deserve more attention from researchers in the future.
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Affiliation(s)
- Wenhao Zhang
- Centre for Translational Medicine, Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
- Department of Clinical Medical, First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Wenzhuo Wei
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
| | - Lijun Ma
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
| | - He Du
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
| | - Anran Jin
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
| | - Jinyi Luo
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China
| | - Xiaoming Li
- Centre for Translational Medicine, Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
- Department of Medical Psychology, School of Mental Health and Psychological Science, Anhui Medical University, Hefei, China.
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Zhao Y, Tan M, Yin Y, Zhang J, Song Y, Li H, Yan L, Jin Y, Wu Z, Yang T, Jiang T, Li H. Comprehensive macro and micro views on immune cells in ischemic heart disease. Cell Prolif 2024; 57. [DOI: pmid: 39087342 doi: 10.1111/cpr.13725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 07/18/2024] [Indexed: 06/06/2025] Open
Abstract
AbstractIschemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end‐stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T‐lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell‐based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell‐targeted therapy for IHD.
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Affiliation(s)
- Yongjian Zhao
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Mingyue Tan
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
- Department of Geriatrics, Southwest Hospital The Third Military Medical University (Army Medical University) Chongqing China
| | - Yunfei Yin
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Jun Zhang
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Yiyi Song
- Suzhou Medical College of Soochow University Jiangsu China
| | - Hang Li
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Lin Yan
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Yifeng Jin
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Ziyue Wu
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Tianke Yang
- Department of Ophthalmology, The First Affiliated Hospital of USTC University of Science and Technology of China Hefei China
| | - Tingbo Jiang
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
| | - Hongxia Li
- Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
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Hamza FN, Mohammad KS. Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments. Pharmaceuticals (Basel) 2024; 17:1591. [PMID: 39770433 PMCID: PMC11679356 DOI: 10.3390/ph17121591] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/20/2024] [Accepted: 11/23/2024] [Indexed: 01/11/2025] Open
Abstract
Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment's immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life.
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Affiliation(s)
- Fatheia N. Hamza
- Department of Biochemistry, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Khalid Said Mohammad
- Department of Anatomy and Genetics, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Bukowski K, Rogalska A, Marczak A. Folate Receptor Alpha-A Secret Weapon in Ovarian Cancer Treatment? Int J Mol Sci 2024; 25:11927. [PMID: 39595996 PMCID: PMC11593442 DOI: 10.3390/ijms252211927] [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: 10/09/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Due to its nonspecific symptoms and unreliable screening tools, EOC is not diagnosed at an early stage in most cases. Unfortunately, despite achieving initial remission after debulking surgery and platinum-based chemotherapy, most patients experience the recurrence of the disease. The limited therapy approaches have encouraged scientists to search for new detection and therapeutic strategies. In this review, we discuss the role of folate receptor alpha (FRα) in EOC development and its potential application as a biomarker and molecular target in designing new EOC screening and treatment methods. We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody-drug conjugates), FDCs (folate-drug conjugates), SMDCs (small molecule-drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug.
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Affiliation(s)
- Karol Bukowski
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland; (A.R.); (A.M.)
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Lok V, Olson-McPeek S, Spiegelhoff G, Cortez J, Detz D, Czerniecki B. Immunotherapies in breast cancer: harnessing the cancer immunity cycle. Expert Opin Ther Targets 2024; 28:925-935. [PMID: 39523444 DOI: 10.1080/14728222.2024.2427038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Immunotherapies have found limited success in breast cancerdue to significant challenges within the tumor that block T-cell activity and function. AREAS COVERED The current review discusses clinically relevant immunotherapeutics and trials within the framework of the cancer-immunity cycle. EXPERT OPINION Current therapies such as antibody-drug conjugates and immune checkpoint blockade require proper biomarker selection, such as PD1 expression and the degree of tumor-infiltrating lymphocyte (TIL) infiltration to subset potential responders. HER2 and other tumor-associated antigens have served as valuable benchmarks for developing novel therapies, such as antibody engagers and CAR T-cells. However, further research is essential to identify and validate new target antigens that can enhance therapeutic efficacy and broaden the clinical applicability of these approaches.
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Affiliation(s)
- Vincent Lok
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
| | - Sy Olson-McPeek
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
| | - Grace Spiegelhoff
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
| | - Jaqueline Cortez
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
| | - David Detz
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
| | - Brian Czerniecki
- Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA
- Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Pata R, Kristeva J, Kosuru B. Pneumonia in Transplant Recipients: A Comprehensive Review of Diagnosis and Management. Cureus 2024; 16:e73669. [PMID: 39544950 PMCID: PMC11562015 DOI: 10.7759/cureus.73669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2024] [Indexed: 11/17/2024] Open
Abstract
Transplant recipients have an increased risk of complications, including graft dysfunction and infections, which can be life-threatening if not recognized early. Pneumonia ranks as one of the most frequent complications in both solid organ and hematopoietic stem cell transplants. Clinical symptoms manifest late during infections in immunocompromised patients. An aggressive approach centered on early confirmatory diagnosis and a low threshold for empiric therapy is often the most effective strategy. The isolation of a pathogen in an upper airway sample does not necessarily mean the same organism is responsible for pneumonia. Viruses such as CMV (cytomegalovirus virus) may function as co-pathogens for opportunistic infections in transplant recipients in addition to causing their own primary infectious syndrome. Furthermore, some viruses exhibit immunomodulatory effects that can affect the graft function. Given the exhaustive list of causative pathogens responsible for pneumonia, the best approach to the diagnosis is to have a conceptual framework that includes a detailed history, such as the type of transplant, degree of immunosuppression, antimicrobial prophylaxis, risk factors, time of presentation since transplantation and the radiographic pattern on the CT chest (computer tomography of the chest). Management depends predominantly on the degree of antimicrobial resistance, drug-to-drug interaction, and adjustments to the immunosuppression.
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Affiliation(s)
- Ramakanth Pata
- Pulmonary and Critical Care Medicine, One Brooklyn Health, New York, USA
- Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center, Cincinatti, USA
| | | | - Bhanu Kosuru
- Internal Medicine, University of Pittsburgh Medical Center (UPMC) East, Monroeville, USA
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Man Y, Liu Y, Chen Q, Zhang Z, Li M, Xu L, Tan Y, Liu Z. Organoids-On-a-Chip for Personalized Precision Medicine. Adv Healthc Mater 2024:e2401843. [PMID: 39397335 DOI: 10.1002/adhm.202401843] [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: 06/01/2024] [Revised: 08/25/2024] [Indexed: 10/15/2024]
Abstract
The development of personalized precision medicine has become a pivotal focus in modern healthcare. Organoids-on-a-Chip (OoCs), a groundbreaking fusion of organoid culture and microfluidic chip technology, has emerged as a promising approach to advancing patient-specific treatment strategies. In this review, the diverse applications of OoCs are explored, particularly their pivotal role in personalized precision medicine, and their potential as a cutting-edge technology is highlighted. By utilizing patient-derived organoids, OoCs offer a pathway to optimize treatments, create precise disease models, investigate disease mechanisms, conduct drug screenings, and individualize therapeutic strategies. The emphasis is on the significance of this technological fusion in revolutionizing healthcare and improving patient outcomes. Furthermore, the transformative potential of personalized precision medicine, future prospects, and ongoing advancements in the field, with a focus on genomic medicine, multi-omics integration, and ethical frameworks are discussed. The convergence of these innovations can empower patients, redefine treatment approaches, and shape the future of healthcare.
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Affiliation(s)
- Yunqi Man
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
| | - Yanfei Liu
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, P. R. China
| | - Qiwen Chen
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, P. R. China
| | - Zhirou Zhang
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
| | - Mingfeng Li
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
| | - Lishang Xu
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
| | - Yifu Tan
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
| | - Zhenbao Liu
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, P. R. China
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Deo AS, Shrijana, S U S, Karun S, Bisaria K, Sarkar K. Participation of T cells in generating immune protection against cancers. Pathol Res Pract 2024; 262:155534. [PMID: 39180801 DOI: 10.1016/j.prp.2024.155534] [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: 02/23/2024] [Revised: 08/09/2024] [Accepted: 08/11/2024] [Indexed: 08/27/2024]
Abstract
T cells are essential to the immune system's reaction. The major job of the immune system is to identify and get rid of any abnormal or malignant cells in the body. White blood cells called T cells coordinate and carry out immunological responses, including identifying and eliminating cancer cells. It mostly consists of two types called helper T-cells and cytotoxic T-cells. Together, they create an efficient reaction against cancer. Both the primary T cell subtype - CD4+ and CD8+ Tcells have specific role to play in our immune system.CD4+ T cells are limited to MHC-II molecules and acts as helper cell by activating and enhancing other immune cells. On the other side CD8+ T cells are called the killer cells as they eradicate the abnormal and contaminated cells and are limited to MHC-I molecules. The malignant cells are destroyed when cytotoxic T cells come into direct contact with them. This happens via number of processes, including TCR recognition, the release of cytotoxic chemicals, and finally the activation of the immune system. T cell receptors on the surface of cytotoxic T cells allow them to identify tumour cells and these T cells release harmful chemicals like perforins and granzymes when they connect to malignant cells. T-cells that have been stimulated release cytokines such as gamma interferon. T-cells can also acquire memory responses that improve their capacity for recognition and response. Helper T-cells contribute to the development of an immune response. It entails coordination and activation as well as the enlistment of additional immune cells, including macrophages and natural killer cells, to assist in the eradication of cancer cells. Despite the fact that the cancer frequently creates defence systems to circumvent their immune response. Together, these activities support the immune surveillance and T-cell-mediated regulation of cancer cells. Treatments like chemotherapy, radiation, and surgery are main ways to treat cancer but immunotherapy has been emerging since last few decades. These immune specific treatments have shown huge positive result. CAR T cell therapy is a promising weapon to fight again blood cancer and it works by focusing on our immune system to fight and eliminate cancer.
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Affiliation(s)
- Anisha Singha Deo
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shrijana
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Sruthika S U
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shreya Karun
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Kashish Bisaria
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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Bartoszewska E, Tota M, Kisielewska M, Skowron I, Sebastianka K, Stefaniak O, Molik K, Rubin J, Kraska K, Choromańska A. Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia. Cells 2024; 13:1596. [PMID: 39329777 PMCID: PMC11430486 DOI: 10.3390/cells13181596] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024] Open
Abstract
Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Maciej Tota
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Monika Kisielewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Izabela Skowron
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Kamil Sebastianka
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Oliwia Stefaniak
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Klaudia Molik
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Jakub Rubin
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Karolina Kraska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Ahmed EN, Cutmore LC, Marshall JF. Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells. Cancers (Basel) 2024; 16:3186. [PMID: 39335157 PMCID: PMC11430534 DOI: 10.3390/cancers16183186] [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: 08/16/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as they fail to recapitulate the immunosuppressive tumor microenvironment characteristic of solid tumors. As CAR T cell monotherapy is unlikely to be curative for many solid tumors, combination therapies must be investigated, for example, stromal remodeling agents and immunomodulators. The evaluation of these combination therapies requires a fully immunocompetent mouse model in order to recapitulate the interaction between the host's immune system and the CAR T cells. This review will discuss the need for improved immunocompetent murine models for the pre-clinical evaluation of CAR T cells, the current use of such models and future directions.
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Affiliation(s)
- Eman N Ahmed
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Lauren C Cutmore
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
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Nassief G, Anaeme A, Moussa K, Mansour AN, Ansstas G. Recent Advancements in Cell-Based Therapies in Melanoma. Int J Mol Sci 2024; 25:9848. [PMID: 39337333 PMCID: PMC11432154 DOI: 10.3390/ijms25189848] [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: 08/19/2024] [Revised: 09/08/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Malignant melanoma outcomes have drastically changed in recent years due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients still experience intolerable side effects, therapy resistance, and disease progression on ICI therapy. Therefore, there remains a need for novel therapeutics that address this gap in treatment options. Cell-based therapies have gained wide attention as a therapeutic option that could address this gap in treatment options for advanced melanoma. These therapies work by extracting certain cell types produced in the human body such as T-cells, modifying them based on a specific target, and transfusing them back into the patient. In the realm of cancer therapy, cell-based therapies utilize immune cells to target tumor cells while sparing healthy cells. Recently, the Food and Drug Administration (FDA) has approved the usage of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, in advanced melanoma. This came following recent results from the C-144-01 study (NCT02360579), which demonstrated the efficacy and safety of TILs in metastatic melanoma patients who otherwise failed on standard ICI/targeted therapy. Thus, the results of this trial as well as the recent FDA approval have proven the viability of utilizing cell-based therapies to fill the gap in treatment options for patients with advanced melanoma. This review aims to provide a comprehensive overview of major cell-based therapies that have been utilized in melanoma by delineating results of the most recent multi-center phase II/ III clinical trials that evaluate the efficacy and safety of major cell-based therapies in melanoma. Additionally, we provide a summary of current limitations in each cell-based therapeutic option as well as a future direction of how to further extrapolate these cell-based therapies in advanced melanoma.
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Affiliation(s)
- George Nassief
- Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO 63110, USA
| | - Angela Anaeme
- Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO 63110, USA
| | - Karen Moussa
- UMKC School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA
| | - Abdallah N Mansour
- Department of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - George Ansstas
- Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO 63110, USA
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