Why do patients with cancer die?

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(8), P. 578 - 589

Published: June 19, 2024

Language: Английский

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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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Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Language: Английский

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CAR-T cell expansion platforms yield distinct T cell differentiation states

Cytotherapy, Journal Year: 2024, Volume and Issue: 26(7), P. 757 - 768

Published: March 12, 2024

With investigators looking to expand engineered T cell therapies such as CAR-T new tumor targets and patient populations, a variety of manufacturing platforms have been developed scale capacity using closed and/or automated systems. Such are particularly useful for solid targets, which typically require higher doses. Although phenotype function key attributes that often correlate with therapeutic efficacy, how influence the final product is currently unknown. We compared 4 commonly used (CliniMACS Prodigy, Xuri W25 rocking platform, G-Rex gas-permeable bioreactor, static bag culture) identical media, stimulation, culture length, donor starting material. Selected CD4+CD8+ cells were transduced lentiviral vector incorporating CAR targeting FGFR4, promising target pediatric sarcoma. observed significant differences in overall expansion over 14-day culture; cultures had highest while Prodigy lowest (481-fold vs. 84-fold, respectively). Strikingly, we also considerable product, significantly enriched CCR7+CD45RA+ naïve/stem central memory (Tn/scm)-like at 46% 16% 13%, respectively. Gene expression analysis showed CAR-Ts more naïve, less cytotoxic exhausted than bag, G-Rex, CAR-Ts, pointed metabolism confirmed via metabolic assays. hypothesized dissolved oxygen level, decreased substantially during 3 days culture, may contribute phenotype. By culturing 1% O2 from day 5 onward, could generate >60% Tn/scm-like cells, longer time hypoxia correlating percentage cells. Intriguingly, our results suggest oxygenation responsible, least part, among bioreactors hypoxic potential strategy prevent differentiation expansion. Ultimately, study demonstrates selection bioreactor system profound effects not only on expansion, but state resulting

Language: Английский

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Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(5), P. e008659 - e008659

Published: May 1, 2024

Background Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation have become an approved standard of care worldwide relapsed refractory malignancies. If CAR-T therapy non-hematological malignancies is to achieve same stage clinical development, then iterative early-phase testing can add value development process evaluating products containing different CAR designs manufactured under differing conditions. Methods We conducted a phase 1 trial third-generation GD2-specific therapy, which has previously been tested in neuroblastoma patients. In this study, GD2-CAR-T was evaluated first time metastatic melanoma patients combination with BRAF/MEK inhibitor as monotherapy colorectal cancer patient fibromyxoid sarcoma. Feasibility safety were determined persistence studies, multiplex cytokine arrays on sera detailed immune phenotyping original products, circulating cells, and, select patients, tumor-infiltrating cells performed. Results demonstrate feasibility manufacturing at point solid show that single intravenous infusion well tolerated no dose-limiting toxicities or severe adverse events. addition, we note significant improvements phenotype, expansion when modified procedure adopted latter 6 recruited 12-patient trial. also evidence cell-mediated activity some expanded subsets myeloid after therapy. Conclusions This report GD2-targeting other cancers such cancer, showing feasibility, activity, but limited effect. Trial registration number ACTRN12613000198729.

Language: Английский

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Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells

Science Advances, Journal Year: 2025, Volume and Issue: 11(2)

Published: Jan. 10, 2025

Chimeric antigen receptor T cells (CART) targeting CD19 through CD28.ζ signaling induce rapid lysis of leukemic blasts, contrasting with persistent tumor control exhibited by 4-1BB.ζ-CART. We reasoned that molecular dynamics at the CART immune synapse (CARIS) could explain differences in their rejection kinetics. observed CD28.ζ-CART engaged brief highly lethal CARIS and mastered serial killing, whereas 4-1BB.ζ-CART formed lengthy relied on robust expansion cooperative killing. analyzed membrane lipid rafts (mLRs) found that, upon engagement, CD28.ζ-CAR molecules rapidly but transiently translocated into mLRs, mobilizing microtubular organizing center lytic granules to CARIS. This enabled fast recovery sensitivity low target site density. In contrast, gradual accumulation 4-1BB.ζ-CAR LFA-1 mLRs built mechanically tonic mediating chronic Fas ligand–based The CD28.ζ- 4-1BB.ζ-CARIS distinct cytolytic behavior can guide engineering more adaptive effective cellular products.

Language: Английский

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Bioactive sphingolipids as emerging targets for signal transduction in cancer development

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(5), P. 189176 - 189176

Published: Sept. 1, 2024

Language: Английский

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Systemic Treatment in Soft Tissue Sarcomas: Are We Making a Difference?

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 889 - 889

Published: March 5, 2025

Soft tissue sarcomas [STSs] are rare tumors of mesodermal origin that arise in diverse tissues such as muscles, fat, and nerves. There over 100 subtypes STS, each with distinct clinical behaviors responses to treatment. Recent advances treatment have moved towards histology-specific approaches, emphasizing the integration pathological, immunohistochemical, molecular features guide Localized STS is primarily treated surgery, often supplemented by neoadjuvant or adjuvant radiation and/or chemotherapy. However, about half patients localized disease will progress an advanced stage, which typically managed systemic therapies including anthracycline-based chemotherapy doxorubicin epirubicin. Despite these treatments, survival rates for most metastatic remain relatively low. While remains mainstay treatment, ongoing research into biology STSs enhancing our understanding approach complex expansion beyond include targeted therapy immunotherapy improve response outcomes. This review focuses on other than gastrointestinal stromal [GISTs], examines current strategies, highlights recent advances, explores future directions sarcoma patients.

Language: Английский

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The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches

Cancers, Journal Year: 2024, Volume and Issue: 16(10), P. 1863 - 1863

Published: May 13, 2024

Neuroblastoma is a peripheral nervous system tumor that almost exclusively occurs in young children. Although intensified treatment modalities have led to increased patient survival, the prognosis for patients with high-risk disease still around 50%, signifying neuroblastoma as leading cause of cancer-related deaths an embryonal and shaped by its origin from cells within neural crest. Hence, usually presents low mutational burden is, majority cases, driven epigenetically deregulated transcription networks. The recent development Omic techniques has given us detailed knowledge evolution, heterogeneity, plasticity, well intra- intercellular molecular communication networks microenvironment. Here, we discuss potential these discoveries emphasis on new modalities, including immunotherapies which hold promise better future regimens.

Language: Английский

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Challenges and overcoming strategies in CAR-T cell therapy for pediatric neuroblastoma

World Journal of Pediatrics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Language: Английский

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