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Advancements in antibody-drug conjugates as cancer therapeutics.

Antibody-drug conjugates (ADCs) represent a promising approach in targeted cancer therapy, combining the targeted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst minimising off-target effects. This review provides a comprehensive analysis of ADCs, encompassing their structural components, mechanisms of action, and clinical applications. It also examines recent technological advancements, particularly in antibody engineering and linker design, aimed at enhancing therapeutic efficacy and safety. The current clinical landscape is outlined, h

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… receptor alpha; GD2, disialoganglioside; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; HIV, Human Immunodeficiency Virus; IB6, interleukin-6; mCRPC, metastatic castration-resistant prostate cancer; IVB, stage 4B; MSLN, mesothelin … interleukin-6; TROP-2, tumor-associated calcium signal transducer 2; FcRH5, Fc receptor-homolog 5; GD2, disialoganglioside; Nectin-4, nectin cell adhesion molecule-4; PDL1, programmed cell death ligand 1; PSMA, prostate-specific membrane antigen; ROR2, tyrosine-protein kinase transmembrane receptor; MSLN, mesothelin …

Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.

T-cell engagers (TCEs) represent an emerging class of immunotherapies that harness T cells' cytotoxic power to eliminate diseased cells-a transformative future therapeutic strategy. TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune h

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… Similarly, a BiTE molecule targeting CD3, P-cadherin (CDH3), and mesothelin (MSLN) addresses the on-target off-tumor toxicity risks, capitalizing on their co-expression in solid tumors and reduced overlap in normal tissues, as confirmed by immunohistochemistry [ 45 ]. … Abstract 7292: HY05350: a trispecific T-cell engager with immune checkpoint inhibitor targeting mesothelin for solid cancer. Cancer Res 2025;85:7292–2. 87. Meoni P, Vintém APB, Cortez-Retamozo VF. et al. …

Carbohydrate Targets for CAR T Cells in Solid Childhood Cancers.

Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside GD2 on the cell surface of neuroblastomas which derive from GD2-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentia

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… Examples for protein antigens targeted by CARs in advanced preclinical or early clinical development are IL13Rα ( 17 ), HER2 ( 18 ), EGFRvIII ( 19 ), CEA ( 20 ), mesothelin ( 21 ), EphA2 ( 22 ). Overall, the range of adequate antigens beyond B lineage markers is limited. … Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. (2014) 2:112–20. 10.1158/2326-6066.CIR-13-0170 22. Yi Z, Prinzing BL, Cao F, Gottschalk S, Krenciute G. …

Advances in CAR-T Cell Therapy in Head and Neck Squamous Cell Carcinoma.

Surgery with the assistance of conventional radiotherapy, chemotherapy and immunotherapy is the basis for head and neck squamous cell carcinoma (HNSCC) treatment. However, with these treatment modalities, the recurrence and metastasis of tumors remain at a high level. Increasingly, the evidence indicates an excellent anti-tumor effect of chimeric antigen receptor T (CAR-T) cells in hematological malignancy treatment, and this novel immunotherapy has attracted researchers' attention in HNSCC treatment. Although several clinical trials have been conducted, the weak anti-tumor effect and the side

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… As early as 2012, Lanitis et al. designed anti-mesothelin CAR-T cells with pure human scFv to overcome the potential issue of immunogenicity, and reported a significant regression of the tumor size in an ovarian cancer xenograft mouse model after CAR-T cell administration [ 97 ]. … Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. Mol. Ther. 2012;20:633–643. doi: 10.1038/mt.2011.256. 98. Lam N., Trinklein N.D., Buelow B., Patterson G.H., Ojha N., Kochenderfer J.N. …

Keyword Index for Volume 107

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… PE 1876 malignant tumours 1761 mammographic density 18 mammography 24 mass screening/methods 1051 mathematical modelling 814 MCM-2 1384 mechanistic PK/PD 814 MED12 1761 medulloblastoma 1144, 1399 melanoma 422, 455, 570, 977, 1498 men 201 meningioma 1702 menopausal hormone therapy 1181 mesothelin …

The broad spectrum of cancer and immunotherapy: achievements and limitations.

Cancer immunotherapy has revolutionized cancer treatment over the past decades, offering renewed hope to patients with previously untreatable malignancies. This therapeutic approach could be categorized into three primary strategies: immune checkpoint blockade, adoptive cell therapy, and cancer vaccines. Immune checkpoint inhibitors have been highly successful in boosting anti-tumour immune responses by blocking the immunosuppressive signals that cancer cells exploit to evade immune surveillance, mainly that exerted by cytotoxic T lymphocytes. Adoptive cell therapy, particularly chimeric antig

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… Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer. Cancer Immunol Immunother CII. (2023) 72:409. doi: 10.1007/s00262-022-03238-w, PMID: 97. Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, et al. … Mesothelin CAR T cells secreting anti-FAP/anti-CD3 molecules efficiently target pancreatic adenocarcinoma and its stroma. Clin Cancer Res Off J Am Assoc Cancer Res. (2024) 30:1859–77. doi: 10.1158/1078-0432.CCR-23-3841, PMID: 101. Cai F, Zhang J, Gao H, Shen H. …

Oncolytic viruses on the cusp of success?: proceedings of the 9th International Conference on Oncolytic Virus Therapeutics

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… Masato Yamamoto (University of Minnesota, Minneapolis) screened an Ad library of peptide ligands in the fiber knob and identified a mesothelin-targeted motif (VITNxxx) for pancreatic cancer and a CD133 motif (TYMLxxx) to target cancer stem cells. …

Keyword Index for Volume 100

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… markers 221 mass screening 1230 massARRAY 344 mastectomy 1048 maximal tolerated dose 1373 Mcm2 protein 1128 mean sojourn time 1198 medical oncology 44 medulloblastoma 1292 MEK 370 melanoma 28, 174, 431, 1245, 1250, 1638 melanoma therapy 322 menarche 538 menopause 538 mental health 908 mesothelin …

The evolving global landscape of first-in-class oncology drug innovation.

First-in-class (FIC) oncology drugs-defined by their novel mechanisms of action or targeting of previously unaddressed molecular targets-have emerged as a leading force in cancer therapeutic innovation. In this Review, we delineate the global landscape of FIC oncology drug approvals between 2009 and 2024 and analyze the evolving characteristics of both approved FIC therapies and potential FIC (PFIC) candidates in clinical development. To clarify the underlying dynamics of this evolution, we construct an analytic framework encompassing four distinct archetypes of FIC development: new targets, n

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… The top most actively pursued targets in the PFIC pipeline include 4-1BB (0.8%), IL-15 (0.8%), mucin 1 (MUC1) (0.7%), CD70 (0.6%), CD276 (0.6%), CD28 (0.6%), CD47 (0.6%), mesothelin (MSLN) (0.6%), and HER3 (0.5%) (Table 3 ). … Top emerging targets by the number of investigational potential first-in-class drugs Targets Number of investigational drugs 4-1BB 12 Interleukin 15 (IL-15) 12 Mucin 1 (Muc1) 11 CD27 ligand (CD27L, CD70) 9 CD276 (B7-H3) 9 Cluster of differentiation 28 (CD28) 9 Cluster of differentiation 47 (CD47) 9 Mesothelin …

Harnessing live vectors for cancer vaccines: Advancing therapeutic immunotherapy.

Cancer vaccines represent a promising approach within immunotherapies. These vaccines are tailored to target tumor-specific antigens, thereby offering a precision approach to cancer treatment. The key principles in developing therapeutic cancer vaccines include identifying appropriate vaccine targets and selecting effective vaccine delivery platforms. These delivery platforms are diverse and have evolved to enhance the immune response. This review explores live cancer vaccines and the biological entities involved. Live cancer vaccines leverage the use of various biological entities to stimulat

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… One such vaccine, CRS-207, expresses mesothelin, a TAA overexpressed in pancreatic, ovarian, and lung cancers. 19 , 23 Initial clinical trials demonstrated its safety and ability to induce mesothelin-specific T-cell responses. 24 However, the Food and Drug Administration (FDA) placed these studies on … Johnson & Johnson (JNJ) also evaluated vaccines targeting epidermal growth factor receptor variant III (EGFRvIII) and mesothelin (JNJ-61757) and multiple prostate cancer antigens (JNJ-61809). …

Cytokine-Engineered Chimeric Antigen Receptor-T Cell Therapy: How to Balance the Efficacy and Toxicity.

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the paradigm in hematological malignancies. However, its efficacy in treating solid tumors remains limited because the immunosuppressive tumor microenvironment (ITME) seriously blocks T cell activation, infiltration, and proliferation. Cytokines, driving potent assisted function by enhanced T cell expansion, persistence, and direct tumor cell killing, have long been acknowledged as promising candidates combined with CAR-T cells to improve treatment outcomes. Despite their preclinical success, significant toxicity occurs in

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… microenvironment linker for activation of T cells ligand‐induced degradation linker of nucleoskeleton and cytoskeleton lysyl oxidase monoclonal antibodies myeloid‐derived suppressor cells major histocompatibility complex matrix metalloproteinases mesenchymal stromal cells murine stem cell virus mesothelin …

Editorial: Community Series in Engineered Immune Cells in Cancer Immunotherapy (EICCI), volume II.

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… This includes identifying and combining multiple target antigens (such as mesothelin, which is relevant in both pathologies), designing “armed” CARs capable of secreting cytokines to counteract immunosuppression, and optimizing cell trafficking. …

T-cell-engaging antibodies for the treatment of solid tumors: challenges and opportunities.

Purpose of reviewT-cell-engaging antibodies or T-cell engagers (TCEs) can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. Until very recently, only one TCE was approved, the CD19/CD3-bispecific blinatumomab. Many new TCEs in late-stage clinical development target various hematopoietic lineage markers like CD20, BCMA, or CD123. Although very compelling single-agent activity of TCEs was observed with various blood-borne cancers, therapy of solid tumor indications has thus far been less successful.Recent findingsThe approval in 2022 of the gp100 peptid

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… Preliminary safety and efficacy of gavocabtagene autoleucel (gavo-cel, TC-210), a T cell receptor fusion construct (TRuC™), in patients with treatment refractory mesothelin overexpressing solid tumors. Cancer Res 2021; 81: (13 Suppl): [abstract CT105]. 9. Subklewe M. BiTEs better than CAR T cells. …

CAR-NK cell therapy for hematological malignancies.

AbstractChimeric antigen receptor (CAR)-natural killer (NK) cells represent a novel cell therapy platform distinguished from CAR T cells by their more favorable safety profile, easier off-the-shelf allogeneic manufacturing and consequent scalability, and their innate cytotoxicity without needing previous sensitization. CAR-NK cells derived from a variety of sources have been used against hematologic malignancies in several clinical trials, showing significant therapeutic responses and efficacy without severe adverse effects. Limitations that are being addressed in CAR-NK cell therapy include c

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… -6 60 Colamartino ABL Lemieux W Bifsha P Efficient and robust NK-cell transduction with baboon envelope pseudotyped lentivector Front Immunol 10 2019 2873 31921138 10.3389/fimmu.2019.02873 PMC6927467 61 Tarannum M Dinh K Vergara J CAR memory-like NK cells targeting the membrane proximal domain of mesothelin … functional responses Nat Immunol 18 11 2017 1197 1206 28920951 10.1038/ni.3838 103 Yang Y Lundqvist A Immunomodulatory effects of IL-2 and IL-15; implications for cancer immunotherapy Cancers (Basel) 12 12 2020 3586 10.3390/cancers12123586 PMC7761238 33266177 104 Jang J Stanojevic M Piccinelli S Mesothelin …

The role of noble bumblebee (Bombus terrestris) queen glycosaminoglycan in aged rat and gene expression profile based on DNA microarray.

IL-1 induces a significant number of metabolic and hematological changes. In experimental animals, IL-1 treatments cause hypotension due to rapid reduction of systemic blood pressure, reduced vascular resistance, increased heart rate and leukocyte aggregations. IL-1 causes endothelial dysfunction, the triggering factor of which may be of a different nature including pathogen infection. This dysfunction, which includes macrophage intervention and increased protein permeability, can be mediated by several factors including cytokines and arachidonic acid products. These effects are caused by the

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… Examples of overexpressed antigens include HER2/neu in breast cancer or ovarian cancer ( 41 ) and mesothelin in brain metastasis tumors ( 42 ). … Katsoulas HL Papamichail M HER-2/neu-derived peptide epitopes are also recognized by cytotoxic CD3(+)CD56(+) (natural killer T) lymphocytes Int J Cancer 98 864 872 2002 10.1002/ijc.10251 11948464 42 Zhenjiang L Rao M Luo X Sandberg E Bartek J Jr Schoutrop E von Landenberg A Meng Q Valentini D Poiret T Mesothelin-specific …

A guide to cancer immunotherapy: from T cell basic science to clinical practice.

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regar

Targeting the gut microbiota to enhance the antitumor efficacy and attenuate the toxicity of CAR-T cell therapy: a new hope?

Chimeric antigen receptor (CAR) -T cell therapy has achieved tremendous efficacy in the treatment of hematologic malignancies and represents a promising treatment regimen for cancer. Despite the striking response in patients with hematologic malignancies, most patients with solid tumors treated with CAR-T cells have a low response rate and experience major adverse effects, which indicates the need for biomarkers that can predict and improve clinical outcomes with future CAR-T cell treatments. Recently, the role of the gut microbiota in cancer therapy has been established, and growing evidence

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… Mesothelin−targeted second generation CAR-T cells inhibit growth of mesothelin-expressing tumors in vivo. Exp Ther Med. (2019) 17:739–47. doi: 10.3892/etm.2018.7015 35. Guedan S, Posey AD, Jr., Shaw C, Wing A, Da T, Patel PR, et al. …

T cell immunotherapy for cervical cancer: challenges and opportunities.

Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infuse

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… At present, mesothelin, CA125, and folate receptors are the most widely studied antigens in these tumor CAR-T cell therapy trials. … Type | antigen | Stage and Result | Host | NCT CAR-T | Mesothelin | Phase I (terminated) | National Institutes of Health Clinical Center, USA | NCT01583686 Only one patient had SD for > 3.5m αPD1-CAR-T | CD22 | Phase I (recruiting) | Fourth Hospital of Hebei Medical University, China | NCT04556669 CAR-T …

Emerging roles for the IL-6 family of cytokines in pancreatic cancer.

Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the exp

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… However, tofacitinib yielded decreased tumour growth and delayed relapse following treatment only in combination with immunotoxins or antibody-drug conjugates targeting mesothelin [ 252 ], a protein up-regulated in PDAC [ 253 , 254 ]. …

Tumor-derived systems as novel biomedical tools-turning the enemy into an ally.

Cancer is a complex illness that presents significant challenges in its understanding and treatment. The classic definition, "a group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body," fails to convey the intricate interaction between the many entities involved in cancer. Recent advancements in the field of cancer research have shed light on the role played by individual cancer cells and the tumor microenvironment as a whole in tumor development and progression. This breakthrough enables the utilization of the tumor and its components as biological

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… Remarkably, EVs have the potential to stimulate the immune system and induce an antitumor immune response through the presentation of tumor-associated antigens (EA, HER2, mesothelin, CD24, EpCAM, etc.) to immune cells, particularly cytotoxic T cells [ 112 – 114 ]. … tumor growth and metastasis ✓ ✓ - - [ 178 ] CD 9 CD9-positive exosomes play a role in the dissemination of CRC ✓ - ✓ ✓ [ 179 ] Ovarian cancer HE4 (Human Epididymis Protein 4) Modulates EGFR-MAPK signaling pathway to influence cancer cell adhesion, migration, and the growth of tumors - ✓ - - [ 180 ] Mesothelin …