From bench to bedside: the history and progress of CAR T cell therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 15, 2023

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by Food and Drug Administration 2017 for treatment pediatric young adult patients with relapsed or refractory acute lymphocytic leukemia. As April 2023, six CAR therapies have been approved, demonstrating unprecedented efficacy B-cell malignancies multiple myeloma. However, adverse events such as cytokine release syndrome immune effector cell-associated neurotoxicity pose significant challenges to therapy. The severity these correlates pretreatment tumor burden, where higher burden results more severe consequences. This observation is supported application CD19-targeted autoimmune diseases including systemic lupus erythematosus antisynthetase syndrome. These indicate that initiating early at low using debulking strategy prior infusion may reduce events. In addition, expensive has limited effectiveness against solid tumors. this article, we review critical steps led groundbreaking explore ongoing efforts overcome challenges. With promise effective safer development, are optimistic broader range will benefit from revolutionary foreseeable future.

Language: Английский

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Development of NK cell-based cancer immunotherapies through receptor engineering

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(4), P. 315 - 331

Published: March 5, 2024

Abstract Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments greatly increased therapeutic potential NK cells by endowing them with enhanced recognition cytotoxic capacities. This review focuses on surface receptor engineering cell therapy discusses its impact, challenges, future directions. Most approaches based chimeric antigen receptors to allow target specific tumor antigens independent human leukocyte restriction. approach has precision potency NK-mediated elimination cells. In addition, T-cell also mediates intracellular epitopes, which broadens range peptides. Indirect peptide been improved optimizing immunoglobulin constant fragment expression signaling. Indeed, engineered an ability recognize destroy coated antibodies, thereby their antibody-dependent cellular cytotoxicity. The promote expansion, persistence, infiltration transferred microenvironment explored. Receptor-based strategies for sustained functionality within environment discussed, these providing perspectives counteract tumor-induced immunosuppression. Overall, led significant advances immunotherapies. As technical challenges addressed, innovative treatments will likely reshape immunotherapy.

Language: Английский

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Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(11), P. 3146 - 3162

Published: Oct. 5, 2023

Language: Английский

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Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor

Science, Journal Year: 2024, Volume and Issue: 384(6703)

Published: June 27, 2024

Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination endogenous PrP halts progression. In this study, we describe Coupled Histone tail for Autoinhibition Release Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable silencing transcription through programmable DNA methylation. Using histone H3 tail-Dnmt3l fusion, CHARM recruits activates methyltransferases, thereby reducing transgene size cytotoxicity. When delivered mouse brain systemic injection adeno-associated virus (AAV), Prnp -targeted ablates expression across brain. Furthermore, have temporally limited implementing kinetically tuned self-silencing approach. potentially represents broadly applicable strategy suppress proteins, including those implicated in other neurodegenerative diseases.

Language: Английский

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Programmable synthetic receptors: the next-generation of cell and gene therapies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 3, 2024

Abstract Cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat diseases. However, concerns over the safety efficacy require to be further addressed in order realize their full potential. Synthetic receptors, synthetic biology tool that can precisely control function therapeutic cells genetic modules, have been rapidly developed applied as powerful solution. Delicately designed engineered, they finetune activities, i.e., regulate production dosed, bioactive payloads by sensing processing user-defined signals or biomarkers. This review provides an overview diverse receptor systems being used reprogram wide applications biomedical research. With special focus on four at forefront, including chimeric antigen receptors (CARs) Notch (synNotch) we address generalized strategies design, construct improve receptors. Meanwhile, also highlight expanding landscape well current challenges clinical translation.

Language: Английский

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Enhancing the safety of CAR-T cell therapy: Synthetic genetic switch for spatiotemporal control

Science Advances, Journal Year: 2024, Volume and Issue: 10(8)

Published: Feb. 23, 2024

Chimeric antigen receptor T (CAR-T) cell therapy is a promising and precise targeted for cancer that has demonstrated notable potential in clinical applications. However, severe adverse effects limit the application of this are mainly caused by uncontrollable activation CAR-T cells, including excessive immune response due to unregulated action time, as well toxicity resulting from improper spatial localization. Therefore, enhance controllability safety, control module cells proposed. Synthetic biology based on genetic engineering techniques being used construct artificial or organisms specific purposes. This approach been explored recent years means achieving therapy. In review, we summarize advances synthetic methods address major both temporal dimensions.

Language: Английский

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Edible mycelium bioengineered for enhanced nutritional value and sensory appeal using a modular synthetic biology toolkit

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 14, 2024

Filamentous fungi are critical in the transition to a more sustainable food system. While genetic modification of these organisms has promise for enhancing nutritional value, sensory appeal, and scalability fungal foods, tools demonstrated use cases bioengineered production by edible strains lacking. Here, we develop modular synthetic biology toolkit Aspergillus oryzae, an fungus used fermented protein production, meat alternatives. Our includes CRISPR-Cas9 method gene integration, neutral loci, tunable promoters. We elevate intracellular levels nutraceutical ergothioneine flavor-and color molecule heme biomass. The strain overproducing is red readily formulated into imitation patties with minimal processing. These findings highlight enhance foods provide useful applications beyond.

Language: Английский

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Integrating bioelectronics with cell-based synthetic biology

Nature Reviews Bioengineering, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

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Advances in Synthetic Immunology for Targeted Treatment of Systemic Autoimmune Diseases: Opportunities, Challenges, and Future Directions

Immuno, Journal Year: 2025, Volume and Issue: 5(1), P. 6 - 6

Published: Jan. 25, 2025

Systemic autoimmune diseases (SAIDs) affect millions worldwide, presenting significant clinical challenges due to their complex pathogenesis and limited treatment options. Traditional immunosuppressive therapies, while effective, often lack precision, leading side effects inadequate disease control. Recent advances in synthetic immunology offer promising avenues for precise, targeted interventions SAIDs. This review examines the latest innovations treating diseases, focusing on engineered immune cells, biologics, gene-editing technologies. It explores therapeutic potential of these approaches modulate tolerance, reduce systemic inflammation, enhance patient-specific efficacy. However, despite developments, remain, including system complexity, safety concerns, regulatory hurdles that may hinder translation. aims consolidate current advancements, address existing barriers, outline future directions management, highlighting immunology’s role transforming landscape

Language: Английский

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

Blood Science, Journal Year: 2023, Volume and Issue: 5(4), P. 237 - 248

Published: Oct. 1, 2023

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 shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune infectious diseases. Despite these advancements, significant challenges pertaining treatment-related toxic reactions relapses persist. Consequently, current research efforts are focused on addressing issues enhance safety reduce relapse rate. This article provides a comprehensive overview present state therapies, achievements, existing challenges, future developments.

Language: Английский

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