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CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions.

Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavi

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… The CARAMBA project is a phase 1/2 clinical trial funded from the European Union's Horizon 2020 program and a key innovation of the study relies on the use of a Sleeping Beauty (SB) transposon system as strategy for CAR T-cell engineering. … Enhanced CAR T-cell engineering using non-viral sleeping beauty transposition from minicircle vectors. Leukemia. (2017) 31:186–94. 10.1038/leu.2016.180 94. Miskey C, Amberger M, Reiser M, Prommersberger S, Beckmann J, Machwirth M, et al. …

From toxicity to immunity: Evaluating CAR-T and conventional therapies in multiple myeloma through quality-adjusted life year (QALY) outcomes.

Multiple myeloma (MM) remains characterized by recurrent relapse and cumulative treatment burden despite major therapeutic advances. This study compared conventional stepwise regimens with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical considerations within a model-based comparative framework. This comparative pharmacoeconomic modeling analysis was based on published clinical trial data. Kaplan-Meier survival curves were digitized to estimate mean overall survival (OS) and progression-free survival (PFS) using area-under-the-curve integration. Treatment costs were calculated b

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… Similarly, the NEX-T process integrates non-viral gene-transfer systems (e.g., Sleeping Beauty transposons) and automated quality-control algorithms, potentially reducing production time to just a few days. 9 , 10 In addition, “off-the-shelf” allogeneic CAR-T products aim to eliminate wait times 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: 560–571. 10.1038/s41434-021-00254-w 11. Moradi V, Omidkhoda A, Ahmadbeigi N. …

A new era in myeloma: the advent of chimeric antigen receptor-T (CAR-T) cells and bispecific antibodies.

T-cell re-directional therapies, including chimeric antigen receptor (CAR)-T cell and bispecific antibodies (BsA), have transformed the treatment landscape to benefit patients with multiple myeloma. A number of these novel therapies has been approved internationally, with CAR-T therapy recently approved in Australia. In this clinical perspective, we describe the development of CAR-T and BsA therapies, highlighting the clinical benefits and risks, together with the significant costs and infrastructure support required for the provision of these therapies to myeloma patients.

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… CARAMBA: a first‐in‐human clinical trial with SLAMF7 CAR‐T cells prepared by virus‐free Sleeping Beauty gene transfer to treat multiple myeloma . …

Integrated Engineering of CAR-T Cells for Solid Tumours.

Chimeric antigen receptor (CAR) T-cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T-cell dysfunction. This review examines the transition from single-axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next-generation CAR-T cells are designed for precise spatiotemporal activation through logic-gated and pharmacologically regulatable receptors, while being reinforced by metaboli

The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead.

Immunotherapy is the upcoming trend in cancer treatment. Traditional cancer treatment methods include surgical resection, radiotherapy, chemotherapy, small molecule targeted drugs, monoclonal antibodies, and hematopoietic stem cell transplantation (HSCT). Surgical resection is useful for early-stage patients but not for metastatic cancer cells; radiotherapy and chemotherapy are more common but produce substantial damage to normal tissues and have poor selectivity. Targeted drugs, including monoclonal antibodies, have better comprehensive efficacy but can also encourage gene mutation of tumor c

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… immunogenicity [ 3 , 43 ] include (1) multitargeted CAR-T cell technologies; (2) Reforms in the manufacture of T cells (e.g., decrease the risks associated with using virus vectors, including DNA damage, and reduce cost and time of production: by replacing them with nonvirus-based technologies, such as Sleeping Beauty …

Alterations in Salivary Proteome following Single Twenty-Minute Session of Yogic Breathing.

Yogic breathing (YB) has been suggested to reduce stress and blood pressure and increase cognitive processes. However, alterations after YB at the molecular level are not well established. Twenty healthy volunteers were randomized into two groups (N = 10 per group): YB or attention controls (AC). The YB group performed two YB exercises, each for ten minutes, for a total of twenty minutes in a single session. AC group read a text of their choice for 20 minutes. Saliva was collected at baseline and at 5, 10, 15, and 20 minutes. Using Mass Spectrometry (MS), we initially found that 22 proteins we

S1PR4-dependent Воздействие этрасимод на первичную активацию миэлоидных иммунных клеток человека.

ИСТОРИЯ ВОПРОСА: Sphingosine-1-phosphate (S1P) и его five Рецепторы S1PR1-5 играть важную роль в миграции, дифференциации и активации различных иммунных клеток. Недавно было утверждено несколько модуляторов S1PR с особой избирательностью для лечения различных подстрекательских заболеваний. Среди них Озанимод, S1PR1/5 Модулятор, утвержденный для лечения язвительного колита и множественных склерозов, и Etrasimod, S1PR1/4/5 Модулятор, утвержденный для лечения язвительного колита. Хронические самовоспалительные заболевания, такие, как вспыльчивые болезни кишечника (ББК) и язвительный колит, характ

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… A CHO-K1 cell line with stable expression of S1PR1 and one with stable expression of S1PR4 was generated using the sleeping beauty method ( Kowarz et al., 2015 ) with the pSBbi-Bla-T8-SNAP-S1PR1 and pSBbi-Bla-T8-SNAP-S1PR4 plasmids (see Supplementary Figure S1 ). …

Immune system and bone microenvironment: rationale for targeted cancer therapies.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune s

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… The great beauty of osteoclast. Arch Biochem Biophys. 2014; 561:13–21. 10.1016/j.abb.2014.08.009. 3. Mori G, D’Amelio P, Faccio R, Brunetti G. The Interplay between the bone and the immune system. Clin Dev Immunol. 2013; 720504. 10.1155/2013/720504. 4. …

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells.

T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and

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… After stimulation, the transgene encoding CAR is transfected to the T cell through viral or non-viral approaches such as retroviral and lentiviral vectors, transposon (including Sleeping Beauty and PiggyBac), and plasmid; however, most clinical trials have employed retroviral vectors for gene transfer … Enhanced CAR T-cell engineering using non-viral sleeping beauty transposition from minicircle vectors. Leukemia (2017) 31(1):186. 10.1038/leu.2016.180 20. Hudecek M, Gogishvili T, Monjezi R, Wegner J, Shankar R, Kruesemann C, et al. …

Symptom experiences and self-management strategies of patients with haematological malignancy undergoing chemotherapy: A qualitative study.

ObjectiveTo explore symptom experiences and self-management strategies from the haematological malignancy patient's perspective.MethodsA qualitative descriptive approach was used to provide a direct and comprehensive understanding of the symptoms experienced and self-management strategies during treatment among patients with haematological malignancy. Fourteen patients with haematologic malignancies who received chemotherapy at a Chinese tertiary hospital were selected using purposeful sampling. Data were collected via semi-structured interviews and one-on-one patient sessions. The collected d

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… (P3) Benefit from symptom management Promoting family relationships In the process of disease treatment, some patients perceived the beauty of life and the value of their family relationships. …

Caregiver's quality of life in advanced cancer: validation of the construct in a real-life setting of early palliative care.

IntroductionEarly palliative care (EPC) improves the quality of life (QoL) of advanced cancer patients and their caregivers. The increasingly widespread use of this care model requires the development of measures supporting its interventions. Although the construct of patient's QoL has been extensively investigated and several QoL measures have been further validated, there is a paucity of data concerning the QoL of the caregiver. In 2018, McDonald and colleagues addressed this issue by interviewing 23 primary caregivers of advanced cancer patients who participated in an EPC randomized clinica

Феноменологическое понимание старения с множественным склерозом.

СПРАВОЧНАЯ ИНФОРМАЦИЯ И ЗАДАЧИ: По мере увеличения продолжительности жизни сообщества, занимающегося множественным склерозом (МС), необходимы новые новшества и понимание того, что такое возраст «здорового». Опираясь на ряд направлений работы по изучению значения и опыта старения с нетрудоспособным состоянием и показав, как и почему люди, стареющие с MS, по-разному ощущают это явление, эта газета развивает литературу по вопросам старения и инвалидности путем (пере) концептуализации того, что «благосостояние» означает для людей, стареющих с MS, и как благополучие может быть повышено или поставле

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… And appreciation of beauty is a very important, it’s hard to describe. Learning is the most fun of anything. And I have been a big gardener up til now. I can no longer garden. I can’t. I just can’t go out in the heat and garden anymore. However, what I can do is I can learn a lot about gardening. …

Advancing Immunotherapy in Chronic Lymphocytic Leukemia.

The treatment of chronic lymphocytic leukemia (CLL) has significantly shifted from chemoimmunotherapy to targeted therapies like Bruton's tyrosine kinase and BCL2 inhibitors. Despite these advancements, CLL remains an incurable disease characterized by immune dysregulation, therapeutic resistance, and cumulative toxicities. To overcome these challenges, novel immunotherapeutic strategies are emerging as fundamentally different approaches that target immune-tumor interactions. These innovations include novel monoclonal antibodies, bispecific antibodies that redirect T cell cytotoxicity, chimeri

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… CARCIK-CD19 is a donor-derived, CD19-targeted, cytokine-induced CAR T-cell therapy engineered using the non-viral Sleeping Beauty transposon system [ 134 ]. A Phase I/II clinical trial evaluating its safety and clinical activity in patients with CLL is currently recruiting (# NCT05869279 ). …

Convergence of mRNA technology and chimeric antigen receptor therapy: targeted technology optimizing targeted therapy.

Engineering cells to express chimeric antigen receptors (CARs) represents a novel approach in cancer immunotherapy, demonstrating remarkable efficacy in the treatment of hematologic malignancies while also encountering numerous challenges. Against the backdrop of the widespread application of COVID-19 mRNA vaccines, the integration of mRNA technology to produce CAR cells and enhance CAR therapies marks the cutting edge of cancer treatment innovation, offering potential solutions to the challenges faced by traditional CAR therapies. This convergence offers distinct advantages. It enables the ge

Next-generation CAR-T therapy for acute myeloid leukemia: bridging innovation with clinical translation.

Acute myeloid leukemia (AML) is a high-risk hematologic malignancy with poor long-term survival and frequent relapse, sustained by leukemic stem cells, antigenic heterogeneity, and an immunosuppressive bone marrow niche. Although chimeric antigen receptor (CAR) T-cell therapy achieves durable responses in B-cell malignancies, its application in AML is restricted by on-target myelotoxicity from antigen overlap with normal progenitors, heterogeneous and dynamic antigen expression, rapid T-cell exhaustion in suppressive microenvironments, limited manufacturing windows with compromised T-cell qual

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… Alternatively, the Sleeping Beauty transposon system combined with an inducible Caspase-9 safety switch allows selective CAR-T elimination upon drug administration, facilitating subsequent allo-HSCT and ensuring hematopoietic reconstitution [ 98 ]. …

Cytokine-induced killer cells: new insights for therapy of hematologic malignancies.

BackgroundCytokine-induced killer (CIK) cells are a novel subgroup of immune effectors, classified as one of the modified T cell-mediated arms for immunotherapy. These cells exert MHC-unrestricted cytotoxicity against both hematological and solid malignancies with low incidence of treatment-related severe complications. This study reviews the application of CIK cells in treating cases with hematologic malignancies.Main bodyCIK cells consist of CD3+/CD56+ natural killer (NK) T cells, CD3-/CD56+ NK cells, and CD3+/CD56- cytotoxic T cells. In this regard, the CD3+/CD56+ NK T cells are the primary

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… Sleeping beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. J Clin Invest. 2020;130(11):6021–33. 126. Zuo S, Wen Y, Panha H, Dai G, Wang L, Ren X, et al. … 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(5):602–13. 129. Rotiroti MC, Buracchi C, Arcangeli S, Galimberti S, Valsecchi MG, Perriello VM, et al. …

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy.

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening co

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… In regard to CAR-T-cell constructs, our group demonstrated that dual-targeted CD19/CD22 CAR-T-cell therapy had a lower incidence of CRS than single-target CD19 CAR-T-cell therapy, especially in severe CRS (≥3 grade CRS). 49 Additionally, Magnani et al. reported that sleeping beauty-engineered CAR-T cells … Sleeping beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. J. Clin. Investig. 2020;130:6021–6033. doi: 10.1172/JCI138473. 51. Turtle CJ, et al. …

Chimeric Antigen Receptors Based on Low Affinity Mutants of FcεRI Re-direct T Cell Specificity to Cells Expressing Membrane IgE.

IgE is the key mediator of allergic responses. Omalizumab, an IgE-specific monoclonal antibody that depletes IgE, is effective for treating severe allergic asthma. The need for frequent administration of the expensive drug, however, limits its applications. Taking advantage of T cell memory, adoptive T cell therapy (ACT) targeting IgE-producing cells has the potential to achieve long-term suppression of IgE and relief of symptoms for severe allergic diseases. The transmembrane form of IgE (mIgE), which is present on all IgE-producing cells, serves as an excellent molecular target for ACT that

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… A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19 . Immunol Rev. ( 2014 ) 257 : 181 – 90 . 10.1111/imr.12137 24329797 PMC4109051 52. Bushman FD . Retroviral integration and human gene therapy . …

Interplay between stress and cancer-A focus on inflammation.

Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that re

CAR-T-Cell-Based Cancer Immunotherapies: Potentials, Limitations, and Future Prospects.

Cancer encompasses various elements occurring at the cellular and genetic levels, necessitating an immunotherapy capable of efficiently addressing both aspects. T cells can combat cancer cells by specifically recognizing antigens on them. This innate capability of T cells has been used to develop cellular immunotherapies, but most of them can only target antigens through major histocompatibility complexes (MHCs). New gene-editing techniques such as clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (CRISPR-cas9) can precisely edit the DNA sequences. CRISPR-c

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… These minicircles use the non-viral sleeping beauty stable transposition of CAR genes derived from minimal supercoiled DNA vectors. Unlike LV, CAR transposons derived from minicircles integrate into safe genomic loci, minimizing mutagenesis and genotoxicity risk. …