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Development of CAR T Cell Therapy in Children-A Comprehensive Overview.

CAR T cell therapy has revolutionized immunotherapy in the last decade with the successful establishment of chimeric antigen receptor (CAR)-expressing cellular therapies as an alternative treatment in relapsed and refractory CD19-positive leukemias and lymphomas. There are fundamental reasons why CAR T cell therapy has been approved by the Food and Drug administration and the European Medicines Agency for pediatric and young adult patients first. Commonly, novel therapies are developed for adult patients and then adapted for pediatric use, due to regulatory and commercial reasons. Both strateg

A Comprehensive Evaluation of CAR-T Cell Gene Therapy, Tracing its Revolutionary Clinical Breakthroughs and Advancements Towards Next-Generation Engineering.

BACKGROUND: CAR-T cell gene therapy has advanced from an experimental concept to a standard curative treatment for selected hematologic malignancies. Substantial clinical evidence has established CAR-T therapy as a cornerstone for relapsed/refractory B-cell malignancies and multiple myeloma, demonstrating durable, long-term remissions. In 2025, the U.S. Food and Drug Administration (FDA) eliminated the Risk Evaluation and Mitigation Strategy (REMS) requirement, reflecting improved clinical management of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome

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… Several early-phase trials targeting solid tumour antigens such as HER2, EGFRvIII, CEA and mesothelin demonstrated limited clinical efficacy or significant on-target toxicities, and none resulted in durable, practice-changing therapeutic approvals (Refs 74 , 75 , 76 ). …

Current landscape of gene-editing technology in biomedicine: Applications, advantages, challenges, and perspectives.

The expanding genome editing toolbox has revolutionized life science research ranging from the bench to the bedside. These "molecular scissors" have offered us unprecedented abilities to manipulate nucleic acid sequences precisely in living cells from diverse species. Continued advances in genome editing exponentially broaden our knowledge of human genetics, epigenetics, molecular biology, and pathology. Currently, gene editing-mediated therapies have led to impressive responses in patients with hematological diseases, including sickle cell disease and thalassemia. With the discovery of more e

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… I/II | NCT04426669 | Recruiting Gastrointestinal neoplasms Gastrointestinal cancer Colorectal cancer Pancreatic cancer Gallbladder cancer Colon cancer Esophageal cancer Stomach cancer | Solid tumor | T cells | PDCD1 | 10 | CRISPR‐Cas9 | Protein and mRNA electroporation | I | NCT03747965 | Unknown Mesothelin‐positive … In addition, some researchers designed “off the shelf” CAR‐T cells against CD19 or mesothelin to treat B‐cell hematological or solid tumors ( NCT03166878 ; NCT03545815 ). …

Chimeric antigen receptor T cell: A cancer immunotherapy.

During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an human epidermal growth factor receptor-2/neu inhibitor, has been developed and accepted widely for management of chronic myeloid leukaemia and breast cancer respectively. Recent development among the various immunotherapies is adoptive cell transfer (ACT). Research on development of various types of ACT immunotherapy is going on, but so far, Chimeric antigen receptors T cell therapy (CAR-T) has achieved the maximum advancement

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… -1) PD-1 knocked down CD19 CAR-T | Acts on CD-19 | CNS B-cell acute lymphocytic leukaemia CD22 | ` | B-cell leukaemia/lymphoma CD123 | | B-cell leukaemia BCMA proteins | Action on Plasma cells, B-cell subtype | Multiple myelomas CD44v6 | T-cell, monocytes, myeloma, Keratinocyte | Multiple myelomas Mesothelin …

Radiometals in Imaging and Therapy: Highlighting Two Decades of Research.

The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for

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… These trials are based on 227 Th-labeled anti-PSMA-HOPO (Bay 2315497) and 227 Th-labeled anti-mesothelin-HOPO for the treatment of PCa ( NCT03724747 ) [ 355 ] and mesothelioma (Bay 2287411), respectively. … Radiopharmaceuticals | Targets | NCT Number ^ | Disease [ 227 Th]Th-anti PSMA (BAY2315497) | PSMA | NCT03724747 (Phase I; ongoing) | Metastatic castration-resistant prostate cancer [ 355 ] [ 227 Th]Th-anti Mesothelin (BAY2287411) | Mesothelin | NCT03507452 (Phase I; completed) | Advanced recurrent serous …

Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer.

For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been ada

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… IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J. Hematol. Oncol. 2021;14:118. doi: 10.1186/s13045-021-01128-9. 36. Brown C.E., Alizadeh D., Starr R., Weng L., Wagner J.R., Naranjo A., Ostberg J.R., Blanchard M.S., Kilpatrick J., Simpson J., et al. … Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Biochem. Biophys. Res. Commun. 2020;524:96–102. doi: 10.1016/j.bbrc.2020.01.053. 92. Cienfuegos-Jimenez O., Vazquez-Garza E., Rojas-Martinez A. …

Endogenous immune recruitment in glioblastoma CAR T therapy: cytokine, myeloid, and chemokine circuitry.

BackgroundGlioblastoma (GBM) has remained relatively unresponsive to immunotherapy, with scattered durable responses reported in early CAR T-cell studies, but without clear benefit at the population level. The major challenge for GBM has been its heterogeneous nature with a significantly immunosuppressive microenvironment that is predominantly composed of myeloid cells, inhibiting T-cell infiltration, function, and providing a rapid pathway for adaptive resistance. The focus of this review is to reposition GBM CAR T-cell therapy as a systems-level issue, turning localized CAR T-cell cytotoxici

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… Haas AR, Tanyi JL, O’Hara MH et al (2019) Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers. Mol Ther J Am Soc Gene Ther 27:1919–1929 58. … Beatty GL, O’Hara MH, Lacey SF et al (2018) Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology 155:29–32 60. …

T-cell Immunotherapies and the Role of Nonclinical Assessment: The Balance between Efficacy and Pathology.

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it

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… Such an approach has been used to test the safety of a mesothelin CAR product where low levels of expression were known on a several normal tissues ( Beatty et al. 2014 ). … Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies . Cancer Immunol Res 2 , 112 – 20 . 24579088 10.1158/2326-6066.CIR-13-0170 PMC3932715 Bedoya F. Frigault M. J. Maus M. V ( 2017 ). …

CAR-T therapy for neuroendocrine neoplasms: a review of molecular targets and clinical translation.

Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies. In metastatic and progressive forms, standard therapies are often ineffective. CAR-T therapy, which has demonstrated remarkable efficacy in hematologic malignancies, is considered a promising approach for NEN treatment, despite significant barriers inherent to solid tumors. This review aims to comprehensively analyze and systematize current scientific data on the development of CAR-T therapy for NENs of various origins. It focuses on relevant molecular targets, preclinical findings demonstrating the efficacy and s

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… A Phase I study evaluated a strategy enhancing CAR-T cell therapy (autologous mesothelin-targeted CAR-T cells) by combining it with the PD-1 checkpoint inhibitor pembrolizumab. … A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with Malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. (2021) 11:2748–63. doi: 10.1158/2159-8290.CD-21-0407, PMID: 91. …

Proceedings from the First Onco Summit: LATAM Chapter, 19-20 May 2023, Rio de Janeiro, Brazil.

The Onco Summit 2023: The Latin American (LATAM) Chapter took place over two days, from 19-20 May 2023, in Brazil. The event aimed to share the latest updates across various oncology disciplines, address critical clinical challenges, and exchange best practices to ensure optimal patient treatment. More than 30 international and regional speakers and more than 300 oncology specialists participated in the Summit. The Summit discussions centered on common challenges and therapeutic advances in cancer care, with a specific focus on the unique obstacles faced in LATAM and examples of adaptable stra

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… Mesothelin-targeted CAR T-cell therapy, in combination with pembrolizumab, is locally administered into the pleural space; however, the application and feasibility of this treatment are limited by the incidences of cytokine release syndrome (CRS) [ 33 ], a complex and lengthy manufacturing process, use … A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 2021;11:2748–2763. doi: 10.1158/2159-8290.CD-21-0407. 34. …

The application, safety, and future of ex vivo immune cell therapies and prognosis in different malignancies.

IntroductionImmunotherapy has revolutionized how cancer is treated. Many of these immunotherapies rely on ex vivo expansion of immune cells, classically T cells. Still, several immunological obstacles remain, including tumor impermeability by immune cells and the immunosuppressive nature of the tumor microenvironment (TME). Logistically, high costs of treatment and variable clinical responses have also plagued traditional T cell-based immunotherapies.MethodsTo review the existing literature on cellular immunotherapy, the PubMed database was searched for publications using variations of the phr

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… 1/2 NCT04511130 | Acute myeloid leukemia | WT1, PRAME, NY-ESO-1, Survivin | Phase 2 NCT03093350 | Breast cancer (metastatic or locally recurrent unresectable disease) | NY-ESO-1, MAGE A4, PRAME, Survivin, SSX2 | Phase 2 NCT03535246 | Cancers positive for at least one of the following antigens: GD2, mesothelin … , P16, MMP, Melan A, MAGE A1, MAGE A3, MAGE A4 | GD2, mesothelin, P16, MMP, Melan P, MAGE A1/A3/A4 | Phase 2 Bispecific antibody armed T cells A more recent development in ex vivo T cell therapy is the development of bispecific antibodies (BsAbs), which utilize a single molecule that has combined the …

CAR-T cell therapy: Where are we now, and where are we heading?

Chimeric antigen receptor (CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies, with 9 CAR-T-cell products currently available. Furthermore, CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune and infectious diseases. Despite these advancements, significant challenges pertaining to treatment-related toxic reactions and relapses persist. Consequently, current research efforts are focused on addressing these issues to enhance the safe

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… circuit produced IL-2 locally, driving effective infiltration of CAR or TCR T-cells into immune-rejection tumor models of pancreatic cancer and melanoma, enhancing immune cell infiltration and reducing systemic toxicity. 111 A preclinical study found that the local injection of CAR-T cells targeting mesothelin … The use of logical gating switches in CAR-T-cell design can further control their activation, improve the specificity of cell killing, and reduce toxic side effects. 71 Logically gated CAR-T cells targeting carcinoembryonic antigen and mesothelin showed specific toxicity against tumor cells expressing …

Learn from antibody-drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy.

Cancer is one of the leading causes of death worldwide due to high heterogeneity. Although chemotherapy remains the mainstay of cancer therapy, non-selective toxicity and drug resistance of mono-chemotherapy incur broad criticisms. Subsequently, various combination strategies have been developed to improve clinical efficacy, also known as cocktail therapy. However, conventional "cocktail administration" is just passable, due to the potential toxicities to normal tissues and unsatisfactory synergistic effects, especially for the combined drugs with different pharmacokinetic properties. The drug

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… Some promising antigens have been identified including CD138 which is expressed in multiple myeloma and a variety of solid tumors, Trop 2 expressed on the cell surface of most solid tumors and mesothelin expressed in pancreatic and ovarian cancers [ 20 , 92 – 96 ]. … Ter Weele EJ Terwisscha van Scheltinga AGT Kosterink JGW Pot L Vedelaar SR Lamberts LE Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89 Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts Oncotarget 2015 6 42081 42090 26536664 10.18632/oncotarget …

CD47-Targeted Therapy in Cancer Immunotherapy: At a Crossroads of Promise and Challenge.

Cluster of differentiation 47 (CD47), an immune checkpoint commonly referred to as the "don't eat me" signal, plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs). Although early enthusiasm drove broad clinical development, recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential. The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategie

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… Targeted CD47 checkpoint blockade using a mesothelin-directed antibody construct for enhanced solid tumor-specific immunotherapy. Cancer Immunol Immunother. 2025;74(7):214. doi: 10.1007/s00262-025-04032-0; 23. Bauer-Smith H, Sudol ASL, Beers SA, Crispin M. …

Tales from the Jazz ASH: highlights from the 2013 American Society of Haematology meeting.

The 55th annual ASH meeting was held in pleasant New Orleans and was the largest in its history, with 22,495 participants coming from 113 nations. A 'bench-to-bedside and back' attitude characterises haematology probably more than any other discipline in medicine and, as usual, this was reflected in the extremely wide breadth of the topics covered, including the last results from clinical trials and cutting-edge advancements in basic science. This year, the balance was arguably skewed: few truly clinical practice-changing results were presented. On the other hand, a great number of basic and t

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… They devised a good manufacturing practice-compatible, sleeping beauty-based protocol, to transduce iPSCs or hESCs with anti-CD19 or anti-mesothelin (to target mesotheliomas) and generate NK cells, which can kill target cells in a HLA non-restricted manner and without prior sensitisation. …

New developments in immunotherapy for SCLC.

Small cell lung cancer (SCLC) is an aggressive form of neuroendocrine neoplasm known for its striking initial response to treatment, followed by fast relapse and refractoriness in response to additional lines of therapy. New advances in immunotherapy are paving the way for more effective treatment strategies and have promising results with early clinical trial data. While SCLC rarely harbors actionable mutations, the receptor DLL3 is extensively present in SCLC, making it a potential target for immunotherapy. Three emerging therapeutic options include bispecific T cell engagers targeting DLL3,

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… Hagel et al 44 performed genome-scale CRISPR-Cas9 screens in mesothelin ( MSLN )-expressing pancreatic cancer cells to investigate intrinsic resistance to CAR-T cell therapy. They found both antigen-dependent and antigen-independent pathways of tumor resistance. …

Nanomedicine Meets Immunotherapy: Advancing Adoptive Cell Therapy with Nanoparticles in the Treatment of Cancer with Sustainability Perspectives.

Immunotherapy has achieved remarkable clinical success in certain cancers, particularly through adoptive cell therapy (ACT), where T cell engineering with chimeric antigen receptor (CAR) has driven major clinical breakthroughs in the treatment of hematologic malignancies. However, efficacy against solid tumors remains limited due to multiple barriers, including the scarcity of tumor-specific antigens, antigen heterogeneity, immunosuppressive tumor microenvironment, and physical obstruction of T cell infiltration by dense extracellular matrix. Nanoparticle (NP)-based approaches can overcome the

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… Overall, this dual mechanism promoted vascular normalization and improved the penetration of both NPs and mesothelin‐targeted CAR T cells, leading to enhanced infiltration and antitumor efficacy in triple‐negative breast cancer models. … Mesothelin is a relevant tumor‐associated antigen; it is a cell‐surface glycoprotein that is highly expressed in multiple cancers, including lung, pancreatic, and ovarian cancer. …

Characteristics of Registered Studies of Chimeric Antigen Receptor Therapies: A Systematic Review.

ImportanceHundreds of chimeric antigen receptor (CAR) therapies are under investigation for hematologic malignant cancers and solid malignant tumors. As the field of modern CAR therapy enters its second decade, clinical trials that demonstrate the efficacy of CAR therapies using randomized clinical trials (RCTs) and/or investigate methods to optimize patient outcomes with commercially available CAR therapies are increasingly important.ObjectiveTo analyze the landscape of registered CAR-related trials with dual focuses on trial methods and intent.Evidence reviewThis systematic review identified

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… Of 182 CAR trials that involved solid malignant tumors (23% of all trials), the most common targets were mesothelin (23 [13%]), members of the epidermal growth factor receptor family (14 [8%]), and the surface disialoganglioside GD2 (14 [8%]); however, 43 other CAR targets in various solid malignant …

Towards Novel Gene and Cell Therapy Approaches for Cervical Cancer.

Cervical cancer is one of the most common malignancies in women, and the majority of cases are caused by infection with high-risk human papilloma virus (HPV) subtypes. Despite effective preventative measures, such as vaccinations against HPV, over 300,000 women die world-wide from cervical cancer each year. Once cervical cancer is diagnosed, treatment may consist of radial hysterectomy, or chemotherapy and radiotherapy, or a combination of therapies dependent upon the disease stage. Unfortunately, overall prognosis for patients with metastatic or recurrent disease remains poor. In these cases,

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… Another trial ( NCT03356795 ) evaluates multiple targets for CAR-T therapy against cervical cancers, including GD2, PSMA, MUC1, and Mesothelin, but no results have been reported to date. … Another study evaluated anti-Mesothelin-directed CAR-T cell therapy in a Phase I/II clinical trial ( NCT01583686 ), but was terminated due to insufficient accrual. …

[Immunotherapy - The New Era of Oncology].

In the field of immunotherapy, essential progress was achieved over the past years partially demonstrating long lasting therapeutic responses in different tumor entities. A better understanding of the interactions between the tumor and the immune system as well as the integration of immunotherapeutic approaches into clinical routine were the foundations for this development. The different approaches intervene on multiple levels of the immune response and directly or indirectly mount the patient's own immune defense against tumor cells. Immunotherapeutic approaches are represented by cytokine t

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… Up to now, trials on CAR-T cell therapies were performed for Her2+ tumors, EGFR+ tumors, CEA+ (carcinoembryonic antigen) tumors, and mesothelin+ tumors 123 124 125 126 . 4. …