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Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions.

Adaptive immunity, orchestrated by B-cells and T-cells, plays a crucial role in protecting the body from pathogenic invaders and can be used as tools to enhance the body's defense mechanisms against cancer by genetically engineering these immune cells. Several strategies have been identified for cancer treatment and evaluated for their efficacy against other diseases such as autoimmune and infectious diseases. One of the most advanced technologies is chimeric antigen receptor (CAR) T-cell therapy, a pioneering therapy in the oncology field. Successful clinical trials have resulted in the appro

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… The sleeping beauty (SB) transposon system is the currently used substitute for viral-based vectors. It has been used to prepare CD19 + CAR T-cells with antitumor properties in vivo and in vitro ( Singh et al., 2015 ; Chicaybam et al., 2019 ). … Then, the genetic material encoding chimeric receptors is introduced into the T-cells via several known methods (such as mRNA transfection), viral vectors (e.g., lentivirus), or sleeping beauty (SB) transposons. The engineered T-cells expressing CARs are then expanded in a bioreactor. …

CAR-T cells in the treatment of multiple myeloma: an encouraging cell therapy.

Multiple myeloma (MM) is a malignant disease of plasma cells that accounts for approximately 10% of all hematological malignancies and is characterized by a clonal proliferation of malignant plasma cells in the bone marrow. Numerous therapeutic strategies, including proteasome inhibitors, immunomodulators, monoclonal antibodies against CD38 and autologous stem cell transplantation, have prolonged the median survival of MM patients. Nevertheless, almost all MM patients suffer disease relapses due to drug resistance and eventually die from MM or MM-related complications. Chimeric antigen recepto

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… In Europe, the phase 1/2 trial CARAMBA (EudraCT identifier 2019‐001264‐30) is investigating a novel CS1-CAR made with virus‐free, advanced Sleeping Beauty Transposon technology, and the results are eagerly awaited ( 50 ). … CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma . Gene Ther . ( 2021 ) 28 : 560–71 . doi: 10.1038/s41434-021-00254-w PMC8455317 33846552 51 Hosen N . Multiple myeloma and integrins . …

T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors.

T-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g., for HLA-A*02:01 and specific tumor targets), leukapheresis, generation of transduced TCR product, lymphodepletion, and infusion of the TCR-based adoptive therapy. In this review, we summarize the current technology and early clinical development of TCR-based therapy in patients with solid tumors. The challenges of TCR-based therapy include those associ

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… And, finally, Ziopharm is moving forward with its “Sleeping Beauty” TCR-T technology programs targeting NY-ESO-1 antigens in patients with multiple solid tumors. … Sleeping Beauty’s non-viral (transposon/transposase) gene transfer system is suited for developing genetically modified TCR therapies that target neoantigens because of its very rapid manufacturing capability Table 3 Selected tumor markers used for TCR-based therapy, function, and tumor types associated …

Conference report on the 28th annual meeting of the European Musculo-Skeletal Oncology Society, 29 April-1 May 2015, Athens.

The 28th Annual Meeting of the European Musculo-Skeletal Oncology Society was organised in Athens by the local host Professor Papagelopoulos and his team. The main objective of the meeting was to focus on recent advances in the diagnosis and treatment of bone and soft tissue sarcomas. The interdisciplinary nature of the meeting was of great value-surgeons, oncologists, pathologists, radiologists, and basic researchers discussed new strategies in the war on sarcoma. This report will highlight the major findings of this successful meeting.

Beyond BCMA: newer immune targets in myeloma.

AbstractThe identification and targeting of B-cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates, chimeric antigen receptor T cells, and T-cell engagers have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved the survival outcomes of patients with relapsed and/or refractory MM compared with previously established strategies and are moving into earlier lines of therapy. Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvag

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… The CAR T cells are generated by the Sleeping Beauty transposon gene transfer system using a virus-free approach. 40 Early findings from the dose-escalation segment of the CARAMBA-1 study were presented at the EBMT-EHA fourth European CAR T-cell Meeting, suggesting that these CAR T cells are safe and … CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Ther. 2021;28(9):560–571. doi: 10.1038/s41434-021-00254-w. 41. Patel K, Bharathan M, Esteva FJ, et al. …

Answering the "Doctor, can CAR-T therapy cause cancer?" question in clinic.

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… Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia. 2017;31(1):186–194. doi: 10.1038/leu.2016.180. 39. Food and Drug Administration . January 2020. …

The biology of stress in cancer: Applying the biobehavioral framework to adolescent and young adult oncology research.

The stress response influences the development and trajectory of cancer through a host of complex neuroimmune mechanisms. Basic, translational, and clinical research has elucidated these biobehavioral connections and offers a new paradigm for scientific investigation and patient care. Using a biobehavioral approach could offer new diagnostic and therapeutic opportunities in oncology, and this approach will be particularly impactful for adolescent and young adult (AYA) patients with cancer. To date, nearly all biobehavioral oncology research has been done in the adult population. And yet, AYAs

Prospects for Development and Commercialisation of Allogeneic CAR-Based Therapies for Autoimmune Disease.

Chimeric antigen receptor (CAR)-T cell therapies represent a promising therapeutic approach for refractory autoimmune diseases. Although autologous CAR-T cells have achieved success thus far, they require expensive, individualised manufacturing, limiting their commercialisation potential. Allogeneic alternatives could overcome these scalability barriers, providing 'off-the-shelf' treatments, although they raise the issues of graft-vs-host reactions and host-mediated rejection. To mitigate such risks, gene-edited αβ T cells or non-alloreactive host cells (e.g., NK cells, γδ T cells) may be used

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… Non-viral vectors represent another option, with both ‘piggyBAC‘ [ 66 , 92 ] and ‘Sleeping Beauty’ [ 137 , 138 ] transposons showing preclinical success. … Although the Sleeping Beauty transposon system is believed to have a low risk of genomic instability, more investigation is needed into the insertional oncogenesis risk associated with this vector system [ 137 ]. …

Usability testing of an electronic patient-reported outcome system linked to an electronic chemotherapy prescribing and patient management system for patients with cancer.

BackgroundPeople affected by cancer experience a wide range of symptoms which have a major impact on their functioning and health-related quality of life (HRQoL). One way to measure the impact of cancer symptoms is through the use of patient-reported outcomes.MethodsAn electronic patient-reported outcome (ePRO) application (ChemoPRO®) was designed to be used by cancer patients to report their symptoms and communicate with their clinical team. Usability testing sessions were conducted with people with lived experience of cancer to understand how real users interact with the ChemoPRO® system. On

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… Having that link with your clinician/clinical team is good (Participant L) Script size right, content tracking, would be brilliant, the beauty of it's not only great for patients and it's a great way to communicate with clinicians. …

Радиум - с момента открытия и до настоящего времени - обзор событий.

После его открытия радий первоначально пропагандировался в качестве терапевтического агента для широкого круга заболеваний, включая расстройства кожи, аллергию, проблемы зрения, боль в суставах и общее средство для укрепления здоровья. Однако последующие исследования продемонстрировали ее значительную радиологическую токсичность и вредное воздействие на здоровье человека. Несмотря на эти риски, более чем через сто лет после его открытия, некоторые радиевые изотопы по-прежнему имеют ограниченное применение в медицинских целях, особенно при лечении конкретных раковых заболеваний. После поглощени

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… The supposedly subtle radiation was supposed to strengthen the body, boost vitality, support the overall healing process, and, more importantly for women, improve beauty through rejuvenation [ 24 , 35 ]. … At that time, cosmetic companies used radioactive materials and falsified data to promote a completely new quality of their products, giving the skin a radiant beauty. Radium was most often added to moisturizing or anti-aging creams [ 22 ]. …

Generating advanced CAR-based therapy for hematological malignancies in clinical practice: targets to cell sources to combinational strategies.

Chimeric antigen receptor T (CAR-T) cell therapy has been a milestone breakthrough in the treatment of hematological malignancies, offering an effective therapeutic option for multi-line therapy-refractory patients. So far, abundant CAR-T products have been approved by the United States Food and Drug Administration or China National Medical Products Administration to treat relapsed or refractory hematological malignancies and exhibited unprecedented clinical efficiency. However, there were still several significant unmet needs to be progressed, such as the life-threatening toxicities, the high

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… Recently, Jaitip et al. optimized and validated a non-viral genetic modification platform based on Sleeping Beauty transposons delivered with minicircles to express CD19 CAR and CRISPR-Cas9 ribonucleoparticles to inactivate allogeneic TCR, they demonstrated these CAR-T cells possessed vigorous antitumor … UNIVERSAL ALLOGENEIC CAR T CELLS ENGINEERED WITH SLEEPING BEAUTY TRANSPOSONS AND CRISPR/CAS9 FOR CANCER IMMUNOTHERAPY . Mol Ther . ( 2022 ) 30 : 3155–75 . doi: 10.1016/j.ymthe.2022.06.006 PMC9552804 35711141 81 Ottaviano G Georgiadis C Gkazi SA Syed F Zhan H Etuk A . …

How can Cytokine-induced killer cells overcome CAR-T cell limits.

The successful treatment of patients affected by B-cell malignancies with Chimeric Antigen Receptor (CAR)-T cells represented a breakthrough in the field of adoptive cell therapy (ACT). However, CAR-T therapy is not an option for every patient, and several needs remain unmet. In particular, the production of CAR-T cells is expensive, labor-intensive and logistically challenging; additionally, the toxicities deriving from CAR-T cells infusion, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been documented extensively. Alternative

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… Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities. J Clin Invest (2020) 130:6021–33. doi: 10.1172/JCI138473 111. Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IGH. … Preclinical efficacy and safety of CD19CAR cytokine-induced killer cells transfected with sleeping beauty transposon for the treatment of acute lymphoblastic leukemia. Hum Gene Ther (2018) 29:602–13. doi: 10.1089/hum.2017.207 117. …

CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond.

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and

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… The European team also developed a unique SLAMF7 CAR-T-cell model, “CARAMBA”, for virus-free CAR gene transfer by utilizing Sleeping Beauty transposon technology. … CARAMBA: A First-in-Human Clinical Trial with SLAMF7 CAR-T Cells Prepared by Virus-Free Sleeping Beauty Gene Transfer to Treat Multiple Myeloma Gene Ther. 2021 28 560 571 10.1038/s41434-021-00254-w 33846552 PMC8455317 65. Leleu X. Martin T. Weisel K. Schjesvold F. Iida S. Malavasi F. Manier S. …

Тонаберсат усиливает цитотоксичность в глиобластоме с помощью темозоломида путем нарушения межклеточной связи через коннексин 43 ингибирование.

Клетки глиобластомы зависят от коннексина 43 (Cx43) на основе данных о разрыве (GJs) для межклеточной связи, позволяющей им интегрироваться в широко разветвленную злокачественную сеть. Несмотря на многообещающие перспективы новой целевой терапии, отсутствие клинически осуществимых ингибиторов GJ препятствует их внедрению в клинической практике. В настоящем исследовании мы изучили тонаберсат (ТО) — лекарство, вызывающее кровоизлияние в мозг и имеющее свойства GJ-ингиберия, с точки зрения его способности разобрать межклеточную связь в сетях глиобластомы. Для изучения функциональной межклеточной

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… The pMuLE ENTR U6‐sgRNA and pMuLE ENTR CMV‐hCas9 L5‐L2 plasmids were then recombined with a Sleeping Beauty transposon plasmid, ‘pMuSE eGFP‐P2A‐PuroR DEST’ [ 35 ], using LR Clonase II Plus (Thermo Fisher Scientific). … G71 cells were cotransfected with the resulting pMuSE U6‐sgRNA+CMV‐hCas9 + RPBSA‐eGFP‐P2A‐PuroR plasmids and the Sleeping Beauty Transposase‐expressing pCMV(CAT)T7‐SB100 plasmid (Addgene, #34879, kindly provided by Zsuzsanna Izsvak) in a 19:1 mass ratio using the Neon Transfection System (Thermo Fisher …

Chimeric antigen receptor therapy for hematological malignancies: a pediatric perspective from leukapheresis to infusion.

Immunotherapy, particularly chimeric antigen receptor T cells (CAR T)s, has changed the landscape of B-cell malignancy treatment and represents a promising approach to cancer therapy. The use of CAR T-based therapy in pediatric patients presents several critical issues such as the quality of the leukapheresis process and the treatment-related toxicity. Nevertheless, the experience with anti-CD19 CAR Ts in treating pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) demonstrated its feasibility and efficacy with a complete response rate greater than 80%. Although CAR T therapy is

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… In particular our group has validated a platform using Sleeping Beauty (SB) transposon system to engineered Cytokine Induced Killer (CIK) cells for the treatment of adult and pediatric patients BCP-ALL ( NCT03389035 , NCT05252403 ) and B-NHL ( NCT05869279 ) 25 . … therapy by transduction of a single leukemic B cell Nat Med 2018 24 10 1499 1503 10.1038/s41591-018-0201-9 30275568 PMC6511988 25 Magnani CF Mezzanotte C Cappuzzello C Bardini M Tettamanti S Fazio G Preclinical Efficacy and Safety of CD19CAR Cytokine-Induced Killer Cells Transfected with Sleeping Beauty …

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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… Other means of genetic engineering that are currently in development include the transposon/transposase system, such as Sleeping Beauty ( 18 ), or Crispr/Cas9 based technology ( 19 ). … Efficient nonviral sleeping beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity . Gene Ther ( 2009 ) 16 ( 8 ): 1042–9 . doi: 10.1038/gt.2009.54 PMC3469249 19494842 19 Legut M Dolton G Mian AA Ottmann OG Sewell AK . …

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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… In general, CAR-T treatment modality is basically artificially producing modified T-cells to target cancer cells, in which T-cells are harvested from a person, genetically modified with insertion of DNA using an inactive lentivirus or other techniques like sleeping beauty transposon (SBT) system or mRNA …

Health Impacts of High BMI in China: Terrible Present and Future.

Temporal trends and future expectations of health effects due to high body mass index (BMI) remain uncertain in China. The trends of high-BMI-related death in China were evaluated and predicted until 2040 using data and methods from the Global Burden of Disease study. The absolute numbers and age-standardized rates of death and disability-adjusted life years (DALYs) were also calculated by age, gender, and cause. From 1990 to 2019, the high-BMI-related death percent, number and rate were all significantly increased in China, and death rate may exceed that globally in the next 10 years. High BM

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… Additionally, women’s beauty-loving nature dictates that they pay more attention to weight management than men, and women are willing to take action to maintain a normal range of BMI. …

Impact of a New Cost-Effectiveness Threshold Implementation on Cancer Formulary Decisions in Jordan.

Rising prices of novel cancer medications are increasing the economic burden from cancer in Jordan, risking the ability of cancer patients to access lifesaving and life-extending treatments. Furthermore, in the absence of a national health technology assessment (HTA) framework, medication prices in Jordan are set based on manufacturers' pricing considerations and not a value proposition. In response to these challenges, King Hussein Cancer Center (KHCC), the de facto national cancer institute, developed a first-in-country, cancer-specific, cost-effectiveness threshold (CET) to aid institutiona

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… Timmins, N, Rawlins, M, Appleby, J (eds) A terrible beauty: a short history of NICE, pp. 154–169. http://www.idsihealth.org/wp-content/uploads/2016/02/A-TERRIBLE-BEAUTY_resize.pdf . Accessed 8 Apr 2020. 25. …

The Treatment-induced Neuropathy Assessment Scale (TNAS): a psychometric update following qualitative enrichment.

BackgroundThe validation of the Treatment-induced Neuropathy Assessment Scale (TNAS v2.0), a patient-reported outcome measure of symptoms associated with cancer treatment-induced peripheral neuropathy (TIPN), was previously reported. Further patient input (qualitative interviewing, cognitive debriefing) suggested that the measure should be modified to better reflect the TIPN experience. We report the performance of a revised version (TNAS v3.0) for assessing TIPN across cancer treatments. This TNAS version incorporates extensive patient input, in accordance with FDA guidance on the development

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… The robust beauty of improper linear models in decision making. Am Psychol. 1979;34:571–582. doi: 10.1037/0003-066X.34.7.571. 13. Cox DR, Fitzpatrick R, Fletcher AE, Gore SM, Spiegelhalter DJ, Jones DR. Quality-of-life assessment: Can we keep it simple? …