Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 6, 2025

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, extension these successes to solid tumors remains limited due several intrinsic challenges, including heterogeneity immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview recent advances in CAR aimed at overcoming obstacles. We discuss importance identification by emphasizing tumor-specific tumor-associated antigens development antigens. Furthermore, highlight key structural innovations, cytokine-armored CARs, protease-regulated CARs engineered chemokine receptors, enhance infiltration activity within microenvironment. Additionally, novel manufacturing approaches, such as Sleeping Beauty transposon system, mRNA-based transfection, vivo production, are discussed scalable solution improve accessibility therapies. Finally, address critical therapeutic limitations, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), suboptimal persistence cells. An examination emerging strategies for countering limitations reveals that CRISPR-Cas9-mediated genetic modifications combination utilizing checkpoint inhibitors can functionality durability. By integrating insights from preclinical models, trials, innovative engineering review addresses their performance tumors.

Language: Английский

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Application of novel CAR technologies to improve treatment of autoimmune disease

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 9, 2024

Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success spurred research into CAR therapies other diseases, including solid tumor cancers autoimmune diseases. Notably, the development of CAR-based treatments diseases shown great progress recently. Clinical trials anti-CD19 anti-BCMA cells in treating severe B cell-mediated like systemic lupus erythematosus (SLE), have lasting remission thus far. targeting autoreactive are beginning clinical mediated autoantigen (CAAR) specifically target eliminate only cells, they promise mucosal pemphigus vulgaris MuSK myasthenia gravis. Regulatory also been developed, which show potential altering affected areas by creating a protective barrier as well helping decrease inflammation. These new applications disease. Novel technologies developed that increase safety, potency, specificity, efficacy therapy. Applying these novel modifications to CARs enhance applicability This review will detail several recently discuss how their application disease improve this emerging field. include logic-gated CARs, soluble protein-secreting modular enable be more specific, reach wider span safer patients, give potent cytotoxic response. revolutionize growing therapies.

Language: Английский

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Charting new paradigms for CAR-T cell therapy beyond current Achilles heels

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 1, 2024

Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T is hindered by several challenges. These include concerns about long-term and complex manufacturing process, as well efficacy factors such tumor escape, exhaustion, immunosuppressive microenvironment. Additionally, safety issues like risk secondary cancers post-treatment, on-target off-tumor toxicity, immune effector responses triggered cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal development, infusion non-activated quiescent T within a 24-hour period, vivo induction cells. This review comprehensively examines clinical challenges outlines strategies to overcome them, aiming chart pathways beyond its current Achilles heels.

Language: Английский

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Advances in Gene Therapy with Oncolytic Viruses and CAR-T Cells and Therapy-Related Groups

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(4), P. 268 - 268

Published: April 10, 2025

Cancer gene therapy is attracting considerable attention as a new treatment method for overcoming intractable cancers. CAR-T cell has already achieved remarkable results, particularly hematological tumors. Because cells can increase within the body, they have advantage of requiring only single administration. In addition, targeting CD19 antigen been established relapsed or refractory disease in young people with CD19-positive acute B-cell leukemia (B-acute lymphoblastic leukemia, B-ALL) and diffuse large lymphoma (DLBCL). addition to therapy, oncolytic viruses represent promising approach cancer treatment, some clinical use others being researched their potential benefits. These infect kill cells, triggering an immune response that helps body recognize fight cancer. Oncolytic virus form immunotherapy uses modified target destroy tumor while potentially stimulating antitumor responses. shown activity trials, approved specific cancers like melanoma. Research ongoing improve efficacy, expand other types, overcome logistical challenges associated delivery. Gene treat diseases caused by recessive disorders cystic fibrosis, hemophilia, muscular dystrophy, sickle anemia, well acquired genetic diseases, such viral infections immunodeficiency syndrome (AIDS).

Language: Английский

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State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment

Cellular Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain the production of drugs, solid resistance, and side effects related treatment. Some cases have been missed during drug preparation due manufacturing issues, prolonged times, high costs. mainly arise from vitro process, so reevaluating this process could minimize number patients. The immune cells are traditionally collected sent laboratory; after several steps, modified express CAR gene before being injected back into patient's body. During vivo method, is introduced inside allows for treatment begin sooner, avoiding potential failures associated In review, we will elaborate on using CAR, examine benefits approach, ultimately present available solutions incorporating practice.

Language: Английский

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Exploring the potential of the convergence between extracellular vesicles and CAR technology as a novel immunotherapy approach

Journal of Extracellular Biology, Journal Year: 2024, Volume and Issue: 3(9)

Published: Sept. 1, 2024

Abstract Cancer therapy is a dynamically evolving field, witnessing the emergence of innovative approaches that offer promising outlook for patients grappling with persistent disease. Within realm therapeutic exploration, chimeric antigen receptor (CAR) T cells as well CAR NK cells, have surfaced novel approaches, each possessing unique attributes and transformative potential. Immune engineered to express CARs recognizing tumour‐specific antigens, shown remarkable promise in treating terminal cancers by combining precision antibody specificity potent cytotoxic function cells. However, their application solid tumours still its nascent stages, presenting major challenges. On same note, distinct immunotherapeutic approach, utilizing on providing advantages safety, manufacturing simplicity, broader scope cancer treatment. Extracellular vesicles (EVs) emerged agents due ability carry crucial biomarkers biologically active molecules, serving vital messengers intercellular communication network. In context cancer, potential EVs lies delivering tumour‐suppressing proteins, nucleic acid components, or targeting drugs precision, thereby redefining paradigm medicine. The fusion technology capabilities has given rise new frontier. EVs, leveraging power alleviate challenges associated live‐cell therapies. are suggested reduce side effects linked cell hold revolutionize penetrance tumours. act carriers pro‐apoptotic molecules RNA enhancing immune responses expanding this review article, we navigate dynamic landscapes, our objective being evaluate comparative efficacy, safety profiles, complexities, clinical applicability.

Language: Английский

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Translational PK–PD model for in vivo CAR‐T‐cell therapy delivered using CAR mRNA‐loaded polymeric nanoparticle vector

Clinical and Translational Science, Journal Year: 2024, Volume and Issue: 17(12)

Published: Dec. 1, 2024

Abstract Autologous chimeric antigen receptor (CAR) T‐cell therapy has demonstrated remarkable response rates, yet its widespread implementation is hindered by logistical, financial, and physical constraints. Additionally, challenges such as poor persistence allorejection are associated with allogeneic cell therapies. An innovative approach involves in vivo transduction of endogenous T‐cells through the administration CAR mRNA encapsulated polymeric nanoparticles (NPs), resulting transient surface expression on circulating T‐cells. This method presents a promising alternative, although dose–exposure–response relationship CAR‐Ts remains poorly elucidated. The nature may necessitate repeated dosing, potentially introducing additional hurdles like cost patient compliance. To address this issue, we have devised translational pharmacokinetic–pharmacodynamic (PK–PD) model that characterizes following mRNA‐encapsulated NP administration, leveraging vitro data alongside critical binding kinetic parameters sourced from literature. Our adequately captures both settings, while incorporating known physiological parameter values exhibiting precise estimation unknown (coefficient variation < 30%). Global sensitivity analyses underscore significance intracellular stability, highlighting linked to free concentration. Model‐based simulations indicate optimizing dose dosing frequency can achieve sustained expression, despite protein characteristic mRNA‐based mechanistic PK–PD holds potential for integration into physiologically‐based pharmacokinetic models, facilitating translation CAR‐T‐cell therapies preclinical studies human applications.

Language: Английский

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Genetic alteration of SJ293TS cells and modification of serum-free media enhances lentiviral vector production

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(2), P. 101270 - 101270

Published: May 21, 2024

Successful cell and gene therapy clinical trials have resulted in the US Food Drug Administration European Medicines Agency approving their use for treatment of patients with certain types cancers monogenetic diseases. These novel therapies, which rely heavily on lentiviral vectors to deliver therapeutic transgenes patient cells, driven additional investigations, increasing demand both pre-clinical current Good Manufacturing Practices-grade viral vectors. To better support studies by improving production methods, we report development a genetically modified HEK293T-based line that is null expression Protein Kinase R Beta-2 microglobulin grows suspension using serum-free media, SJ293TS-DPB. Absence increased anti-sense vector titers more than 7-fold, while absence microglobulin, key component major histocompatibility complex class I molecules, has been reported reduce immunogenicity particles. Furthermore, describe an improved methodology culturing SJ293TS-DPB facilitates expansion, reduces handling, increases 2-fold compared previous methods. stably produced over 4 months generated efficiently transduce healthy human donor T cells CD34+ hematopoietic stem cells.Graphical abstract

Language: Английский

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CAR T Cell Nanosymbionts: Revealing the Boundless Potential of a New Dyad

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 13157 - 13157

Published: Dec. 7, 2024

Cancer treatment has traditionally focused on eliminating tumor cells but faces challenges such as resistance and toxicity. A promising direction involves targeting the microenvironment using CAR T cell immunotherapy, which shown potential for treating relapsed refractory cancers is limited by high costs, resistance, toxicity, especially in solid tumors. The integration of nanotechnology into ICAM therapy, a concept we have named "CAR nanosymbiosis", offers new opportunities to overcome these challenges. Nanomaterials can enhance delivery, manufacturing, activity modulation, microenvironment, providing better control precision. This approach aims improve efficacy against tumors, reduce associated toxicities, ultimately patient outcomes. Several studies results, developing this therapy further essential increasing its accessibility effectiveness. Our "addition subtraction model" synthesizes multifaceted elements unified strategy advance cancer paradigms.

Language: Английский

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