Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 19, 2022

Abstract Cancers are highly complex diseases that characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming system play critical roles in tumor initiation progression. Immunotherapy aims to reactivate antitumor overcome escape mechanisms tumors. Represented checkpoint blockade adoptive cell transfer, immunotherapy has seen tremendous success clinic, with capability induce long-term regression some tumors refractory all other treatments. Among them, blocking therapy, represented PD-1/PD-L1 inhibitors (nivolumab) CTLA-4 (ipilimumab), shown encouraging therapeutic effects treatment various tumors, such as non-small lung cancer (NSCLC) melanoma. In addition, advent CAR-T, CAR-M novel methods, entered a new era. At present, evidence indicates combination multiple methods may be one way improve effect. However, overall clinical response rate still needs improvement, which warrants development designs well discovery biomarkers can guide prescription these agents. Learning from past failure both basic research is for rational design studies future. this article, we describe efforts manipulate against discuss different targets types exploited promote

Language: Английский

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Advances in Universal CAR-T Cell Therapy

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 6, 2021

Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist autologous CAR-T therapy, such as high costs, long manufacturing periods, and restricted sources. The development of a universal (UCAR-T) is an attractive breakthrough point that may overcome most these drawbacks. Here, we review the progress challenges focusing on comprehensive comparison UCAR-T original therapy. Furthermore, summarize developments concerns about safety efficiency Finally, address other immune cells, which might be promising candidates complement for cells. Through detailed overview, describe current landscape explore prospect

Language: Английский

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

Frontiers in Bioengineering and Biotechnology, Journal Year: 2022, Volume and Issue: 10

Published: June 22, 2022

Adaptive immunity, orchestrated by B-cells and T-cells, plays a crucial role in protecting the body from pathogenic invaders can be used as tools to enhance body’s defense mechanisms against cancer genetically engineering these immune cells. Several strategies have been identified for treatment evaluated their efficacy other diseases such autoimmune infectious diseases. One of most advanced technologies is chimeric antigen receptor (CAR) T-cell therapy, pioneering therapy oncology field. Successful clinical trials resulted approval six CAR-T cell products Food Drug Administration hematological malignancies. However, there various obstacles that limit use CAR first line mechanism cancer. Various innovative therapeutic designs preclinical trial settings demonstrated much potential development. Such testing suitability CARs solid tumors HIV are showing promising results. In addition, new solutions proposed overcome limitations this therapy. This review provides an overview current knowledge regarding novel technology, including structure, different applications, limitations, solutions.

Language: Английский

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Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(3), P. e005583 - e005583

Published: March 1, 2023

Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types hematological malignancies, but shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells’ delivery and antitumor activity. We previously showed blocking vascular endothelial growth factor (VEGF) signaling can normalize vessels murine human tumors, including GBM, breast, liver, rectal carcinomas. Moreover, we demonstrated normalization improve CD8+ T immunotherapy breast cancer models mice. In fact, US FDA (Food drug administration) has approved seven different combinations anti-VEGF drugs immune checkpoint blockers for kidney, lung endometrial cancers past 3 years. Here, tested hypothesis therapy immunocompetent mice bearing orthotopic GBM engineered two syngeneic mouse cell lines (CT2A GSC005) express EGFRvIII—one most common neoantigens GBM—and CAR recognize EGFRvIII. found anti-mouse VEGF antibody (B20) improved infiltration distribution throughout TME, delayed growth, prolonged survival GBM-bearing compared EGFRvIII-CAR-T alone. Our findings provide compelling data a rationale clinical evaluation agents patients.

Language: Английский

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The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors

Cancer Letters, Journal Year: 2024, Volume and Issue: 591, P. 216871 - 216871

Published: April 10, 2024

Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to "living drugs" they not only target tumor directly, but also induce long-term immune memory that has potential provide long-lasting protection. CD19.CAR-T have achieved complete response rates over 90% for acute lymphoblastic leukemia and 60% non-Hodgkin's lymphoma. However, rate solid tumors remains extremely low side effects potentially severe. In this review, we discuss limitations microenvironment poses application solutions being developed address these limitations, hope near future, therapy can attain same success now seen clinically hematological malignancies.

Language: Английский

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The Progress and Prospects of Immune Cell Therapy for the Treatment of Cancer

Cell Transplantation, Journal Year: 2024, Volume and Issue: 33

Published: Jan. 1, 2024

Immune cell therapy as a revolutionary treatment modality, significantly transformed cancer care. It is specialized form of immunotherapy that utilizes living immune cells therapeutic reagents for the cancer. Unlike traditional drugs, therapies are considered “living drugs,” and these products currently customized require advanced manufacturing techniques. Although chimeric antigen receptor (CAR)-T have received tremendous attention in industry regarding hematologic malignancies, their effectiveness treating solid tumors often restricted, leading to emergence alternative therapies. Tumor-infiltrating lymphocytes (TIL) therapy, cytokine-induced killer (CIK) dendritic (DC) vaccines, DC/CIK designed use body’s natural defense mechanisms target eliminate cells, usually fewer side effects or risks. On other hand, therapies, such receptor-T (CAR-T) cell, T (TCR)-T, receptor-natural (CAR-NK), CAR-macrophages (CAR-M) typically utilize either autologous stem allogeneic xenogeneic genetically modified which higher levels manipulation high risk. These high-risk hold special characteristics tumor targeting signal transduction, triggering new anti-tumor responses. Recently, significant advances been achieved both basic clinical researches on mechanisms, product designs, technological innovations. With swift integration innovation landscape, key future development directions emerged. To meet demands advancements cancer, we comprehensively systematically investigate progress this study. Based methodological features analyzed main technical advantages transformation risks associated with We also forecasted application prospects, providing references relevant enterprises necessary information make informed decisions R&D direction selection.

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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Enhancing precision in cancer treatment: the role of gene therapy and immune modulation in oncology

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 13, 2025

Gene therapy has long been a cornerstone in the treatment of rare diseases and genetic disorders, offering targeted solutions to conditions once considered untreatable. As field advances, its transformative potential is now expanding into oncology, where personalized therapies address immune-related complexities cancer. This review highlights innovative therapeutic strategies, including gene replacement, silencing, oncolytic virotherapy, CAR-T cell therapy, CRISPR-Cas9 editing, with focus on their application both hematologic malignancies solid tumors. CRISPR-Cas9, revolutionary tool precision medicine, enables precise editing cancer-driving mutations, enhancing immune responses disrupting tumor growth mechanisms. Additionally, emerging approaches target ferroptosis—a regulated, iron-dependent form death—offering new possibilities for selectively inducing death resistant cancers. Despite significant breakthroughs, challenges such as heterogeneity, evasion, immunosuppressive microenvironment (TME) remain. To overcome these barriers, novel like dual-targeting, armored cells, combination checkpoint inhibitors ferroptosis inducers are being explored. rise allogeneic “off-the-shelf” offers scalable more accessible options. The regulatory landscape evolving accommodate advancements, frameworks RMAT (Regenerative Medicine Advanced Therapy) U.S. ATMP (Advanced Therapy Medicinal Products) Europe fast-tracking approval therapies. However, ethical considerations surrounding CRISPR-based editing—such off-target effects, germline ensuring equitable access—remain at forefront, requiring ongoing oversight. Advances non-viral delivery systems, lipid nanoparticles (LNPs) exosomes, improving safety efficacy By integrating innovations addressing concerns, poised revolutionize cancer treatment, providing durable, effective,

Language: Английский

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Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 23, 2022

Chimeric antigen receptor T cell (CAR-T) therapy demonstrated remarkable success in long-term remission of cancers and other autoimmune diseases. Currently, six products (Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, Carvykti) are approved by the US-FDA for treatment a few hematological malignancies. All autologous CAR-T therapies, where delivery CAR, which comprises scFv (single-chain variable fragment) derived from monoclonal antibodies tumor target recognition is through lentiviral vector. Although available therapies yielded impressive response rates large number patients comparison to conventional strategies, there potential challenges field limit their efficacy. One major induction humoral and/or cellular immune elicited due domain CAR construct, non-human origin majority commercially products. Generation anti-CAR may lead clearance therapeutic cells, increasing likelihood relapse lower cells efficacy upon reinfusion. These responses influence expansion persistence, that might affect overall clinical response. In this review, we will discuss impact immunogenicity transgene on outcomes. Finally, review highlight mitigation strategies immunogenic CARs improve outcome.

Language: Английский

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An m6A/m5C/m1A/m7G-Related Long Non-coding RNA Signature to Predict Prognosis and Immune Features of Glioma

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: May 26, 2022

Background: Gliomas are the most common and fatal malignant type of tumor central nervous system. RNA post-transcriptional modifications, as a frontier hotspot in field epigenetics, have attracted increased attention recent years. Among such methylation is abundant, encompasses N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1 methyladenosine (m1A), 7-methylguanosine (m7G) methylation. Methods: RNA-sequencing data from healthy tissue low-grade glioma samples were downloaded The Cancer Genome Atlas database along with clinical information mutation glioblastoma samples. Forty-nine m6A/m5C/m1A/m7G-related genes identified an m6A/m5C/m1A/m7G-lncRNA signature co-expressed long non-coding RNAs selected. Least absolute shrinkage selection operator Cox regression analysis was used to identify 12 lncRNAs associated prognostic characteristics their correlation immune function drug sensitivity analyzed. Furthermore, Chinese Glioma dataset for model validation. Results: A total (AL080276.2, AC092111.1, SOX21-AS1, DNAJC9-AS1, AC025171.1, AL356019.2, AC017104.1, AC099850.3, UNC5B-AS1, AC006064.2, AC010319.4, AC016822.1) construct survival prognosis model, which had good independent prediction ability patients glioma. Patients divided into low high m6A/m5C/m1A/m7G-LS groups, latter poor prognosis. In addition, enabled improved interpretation results enrichment analysis, well informing immunotherapy response different subgroups. Conclusion: this study we constructed established nomogram can accurately predict provides direction toward promising strategies future.

Language: Английский

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